Unraveling Hematopoiesis through the Lens of Genomics
Open accessAbstract
Hematopoiesis has long served as a paradigm of stem cell biology and tissue homeostasis. In the past decade, the genomics revolution has ushered in powerful new methods for investigating the hematopoietic system that have provided transformative insights into its biology. As part of the genomics revolution, increasingly accurate deep sequencing and novel methods of cell tracking have revealed hematopoiesis to be more of a continuous and less of a discrete and punctuated process than originally envisioned. In part, this continuous nature of hematopoiesis is made possible by the emergent outcomes of vast, interconnected regulatory networks that influence cell fates and lineage commitment. It is also becoming clear how these mechanisms are modulated by genetic variation present throughout the population. This review describes how these recently uncovered complexities are reshaping our concept of tissue development and homeostasis, while opening up a more comprehensive future understanding of hematopoiesis.
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TL;DR
This review argues that the genomics revolution has reshaped the classical hierarchical model of hematopoiesis into a "continuum" model, in which differentiation proceeds largely continuously rather than through discrete punctuated fate decisions. It surveys single-cell genomics, lineage barcoding, regulatory profiling, and human genetics as complementary tools for understanding hematopoietic cell states, fates, and their modulation by genetic variation.
Key findings
- Single-cell RNA-seq of the mammalian hematopoietic system typically yields a largely continuous distribution of cells from HSCs through mature lineages, supporting a "continuum model" that diverges from the classic punctuated lineage tree; however, functional perturbations reveal distinct transition points, suggesting punctuated transitions may still exist across the continuous landscape.
- Cell barcoding combined with scRNA-seq shows that early fate biases in HSPCs significantly impact eventual fate, that CMPs are heterogeneous and have already made deterministic fate choices, and that multiple differentiation routes can produce the same lineage (e.g., monocytes).
- Different lineage-tracing methods disagree on HSC contribution to steady-state hematopoiesis: transposon and genetic barcoding suggest MPPs carry most of the burden, while Cre-lox barcoding and direct fluorescent labeling show consistent, significant HSC contribution; the review concludes there is substantial evidence for regular HSC contributions.
- Over ten thousand loci have been defined across the allelic spectrum explaining inter-individual variation in blood cell traits; variants influencing multiple traits tend to map to chromatin accessible in early HSPCs, while lineage-restricted variants map to more mature committed cells.
Methods
- Narrative review of adult hematopoiesis in mice and humans, synthesizing literature on single-cell genomics, lineage tracing/barcoding, transcription factor and chromatin profiling (ChIP-seq, ATAC-seq, DNase hypersensitivity), 3D proximity ligation methods, and human population/rare-variant genetics.
- No primary data or new experiments; the paper reviews and interprets published studies, including historical work (e.g., ~10,000 HSCs estimated in mouse by competitive BM transplant; 500 billion cells generated daily in humans).
Limitations
- Stated: the review focuses largely on adult hematopoiesis in mice and humans, excluding developmental and cross-organism differences covered elsewhere; it focuses on intrinsic regulation, with microenvironment/niche covered in other reviews.
- Stated: in the absence of fate tracking, all inferred biases in native hematopoiesis are speculative; barcoding efficiencies may underrepresent rare populations, and labeling saturation may overrepresent HSCs sharing barcodes with progenitors.
- Stated: gene expression alone may be insufficient to distinguish discrete cell populations; genetic barcoding/inducible labeling cannot be used for in vivo human hematopoiesis, and human genomic mutation rates are low, limiting clone-tracking resolution.
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Cites
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Claims the paper makes
0 of 115 cited sources checked · 0 supported · 0 flagged
- Findingcitation
Variants that influence multiple blood traits tend to impact chromatin that is accessible in early hematopoietic stem and progenitor cells.
“For instance, variants that influence multiple blood traits tend to impact chromatin that is accessible in early HSPCs.”
Quote in the paperSubstantial claim - Findingcitation
Variants that modify function only within single hematopoietic lineages tend to map to more mature, lineage-committed cells.
“Variants that modify function only within single hematopoietic lineages instead tend to map to more mature, lineage committed cells.”
Quote in the paperSubstantial claim - Premisecitation
There is support for cells expressing distinct modules of transcriptional programs that cooperate to subtly and continuously prime cells to differentiate along target lineages.
“It is still unclear how continuous lineage decisions could be made, but there is support for cells expressing distinct modules of transcriptional programs that cooperate to subtly and continuously prime cells to differentiate along target lineages (Giladi et al., 2018; Velten et al., 2017).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
Single-cell genomic approaches have produced compelling evidence that observed cellular heterogeneity reflects downstream lineage decisions.
“Finally, while single-cell genomic approaches have produced compelling evidence that observed cellular heterogeneity reflects downstream lineage decisions (Herring et al., 2018; La Manno et al., 2018; Rodriguez-Fraticelli et al., 2018), in the absence of fate tracking, all inferred biases in native hematopoiesis are speculative (Pina et al., 2012; Velten et al., 2017).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationreasoning
Transcriptional continuity has contributed to a revised continuum model of hematopoiesis.
“This transcriptional continuity has contributed to a revised model of the hematopoietic lineage tree, often termed a continuum model of hematopoiesis (Figure 1B).”
Quote in the paperSubstantial claim
- Interpretationcitation
In the continuum model, differentiation from HSCs to progenitors to mature functional cells occurs constantly and without distinct punctuated phenotypic changes.
“In this continuum model, the process of differentiation from HSCs to progenitors to mature functional cells is envisioned as occurring constantly and without the distinct punctuated phenotypic changes that exist within the classic model of hematopoiesis (Laurenti and Göttgens, 2018; Velten et al., 2017).”
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- cites Velten et al., 2017 source
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- Interpretationreasoning
Original cell states largely reflect arbitrary borders created by limited samplings of hematopoiesis rather than biologically genuine cell states.
“The original states themselves would also largely reflect the arbitrary borders created by limited samplings of hematopoiesis rather than biologically genuine cell states.”
Quote in the paperSubstantial claim - Premisecitation
scRNA-seq profiling of the mammalian hematopoietic system typically produces a largely continuous distribution of cells from the earliest HSCs through the characteristic hematopoietic lineages.
“When computationally reconstructed, single-cell RNA sequencing (scRNA-seq) profiling of the mammalian hematopoietic system typically produces a largely continuous distribution of cells from the earliest HSCs through the characteristic hematopoietic lineages (Nestorowa et al., 2016; Olsson et al., 2016; Paul et al., 2015; Pellin et al., 2019; Tusi et al., 2018; Weinreb et al., 2020).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationnone given
Mechanisms of hematopoiesis are modulated by genetic variation present throughout the population.
“It is also becoming clear how these mechanisms are modulated by genetic variation present throughout the population.”
Quote in the paperNot a substantial claim - Interpretationcitation
In the absence of fate tracking, all inferred biases in native hematopoiesis are speculative.
“Finally, while single-cell genomic approaches have produced compelling evidence that observed cellular heterogeneity reflects downstream lineage decisions (Herring et al., 2018; La Manno et al., 2018; Rodriguez-Fraticelli et al., 2018), in the absence of fate tracking, all inferred biases in native hematopoiesis are speculative (Pina et al., 2012; Velten et al., 2017).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
Coupling gene expression variation with assessment of different subpopulations has enabled distinct functional groups to be defined.
“Coupling gene expression variation with assessment of different subpopulations has enabled distinct functional groups to be defined (Pietras et al., 2015).”
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- Interpretationcitation
Gene expression variation may cause enough transcriptome diversity in scRNA-seq that distinct populations of cells blend together and become indistinguishable.
“Of course, gene expression can vary widely across phenotypically similar cells (Kaufmann and van Oudenaarden, 2007; Marinov et al., 2014), which may cause enough transcriptome diversity in scRNA-seq that distinct populations of cells blend together and become indistinguishable from each other.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Kaufmann and van Oudenaarden, 2007
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- cites Marinov et al., 2014 source
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- Premisecitation
Gene expression can vary widely across phenotypically similar cells.
“Of course, gene expression can vary widely across phenotypically similar cells (Kaufmann and van Oudenaarden, 2007; Marinov et al., 2014), which may cause enough transcriptome diversity in scRNA-seq that distinct populations of cells blend together and become indistinguishable from each other.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Kaufmann and van Oudenaarden, 2007
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- cites Marinov et al., 2014 source
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- Interpretationcitation
Deep sequencing and cell tracking have revealed hematopoiesis to be more continuous and less discrete and punctuated than originally envisioned.
“As part of the genomics revolution, increasingly accurate deep sequencing and novel methods of cell tracking have revealed hematopoiesis to be more of a continuous and less of a discrete and punctuated process than originally envisioned.”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Both scRNA-seq and single-cell transplant experiments suggest significant heterogeneity in the lineage commitment of HSCs and other progenitors that otherwise appear to be functionally similar.
“Both scRNA-seq and single-cell transplant experiments suggest significant heterogeneity in the lineage commitment of HSCs and other progenitors that otherwise appear to be functionally similar (Dong et al., 2020).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Dong et al., 2020 source
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- Interpretationnone given
Signatures of this differentiation route decision are maintained within mature cells.
“Signatures of this differentiation route decision are even maintained within mature cells.”
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Early studies of hematopoiesis relied on genetically ablating the function of key master transcription factors or epigenetic regulators in mice to assess their physiological roles.
“These studies often relied on genetically ablating the function of key master TFs or epigenetic regulators, such as GATA1, SPI1 (PU.1), CEBPA, GFI1, BMI1, IKZF1 (Ikaros), and ETV6 in mice to assess their physiological roles in hematopoiesis (Doulatov et al., 2012; Fujiwara et al., 1996; Hock et al., 2004a, 2004b; Lessard and Sauvageau, 2003; Nichogiannopoulou et al., 1999; Park et al., 2003; Scott”
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In some elderly individuals, HSCs acquire oncogenic mutations that allow them to outcompete their neighbors and clonally expand.
“However, in some elderly individuals, HSCs acquire oncogenic mutations that allow them to outcompete their neighbors and clonally expand.”
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As these HSCs clonally expand, they can account for a substantial fraction of steady state hematopoiesis, termed clonal hematopoiesis of indeterminate potential (CHIP).
“As these HSCs clonally expand, they can account for a substantial fraction of steady state hematopoiesis, termed clonal hematopoiesis of indeterminate potential (CHIP) (Busque et al., 1996; Champion et al., 1997; Vas et al., 2012).”
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The combination of scRNA-seq and cell barcoding has directly demonstrated that early fate biases in hematopoietic stem and progenitor cells significantly impact eventual fate.
“While cell-sorting based methods often show a multipotent HSC and progenitor compartment that gives rise to unipotent lineage-committed cells (Notta et al., 2016), the combination of scRNA-seq and cell barcoding has now directly demonstrated that the early fate biases in hematopoietic stem and progenitor cells (HSPCs) significantly impact eventual fate (Weinreb et al., 2020).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Weinreb et al., 2020 source
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- Interpretationnone given
Genetic barcoding or inducible labeling systems cannot be used to study in vivo human hematopoiesis.
“Unfortunately, genetic barcoding or inducible labeling systems, while powerful, cannot be used to study in vivo human hematopoiesis.”
Quote in the paperNot a substantial claim - Premisecitation
More recently, genomic approaches have helped to unravel the mechanisms by which these factors alter hematopoietic cell differentiation.
“More recently, genomic approaches have helped to unravel the mechanisms by which these factors alter hematopoietic cell differentiation (Göttgens, 2015).”
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- Interpretationreasoning
Highly detailed data from long-range chromatin interactions has enabled large networks of interacting elements to be generated that begin to explain phenotypic diversity within different hematopoietic cell compartments.
“The resulting highly detailed and rich data has enabled large networks of interacting elements to be generated that begin to explain the phenotypic diversity that seemingly exists within different hematopoietic cell compartments.”
Quote in the paperSubstantial claim - Premisecitation
There are multiple differentiation paths that cells can follow to produce the same lineage, such as is observed for monocyte differentiation.
“Further complicating the picture of hematopoiesis, it appears that there are multiple differentiation paths that cells can follow to produce the same lineage, such as is observed for monocyte differentiation (Figure 2) (Weinreb et al., 2020).”
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- Interpretationreasoning
Lineage tracing is not sufficient to explain the mechanisms underlying cell decisions during hematopoiesis.
“While lineage tracing will help to understand the outcomes of cell decisions during hematopoiesis, they are not sufficient to explain the mechanisms underlying these decisions.”
Quote in the paperSubstantial claim - Premisecitation
HSCs containing oncogenic mutations can overtake most of the hematopoietic system without transforming into leukemia.
“The phenomenon also appears to be counterintuitively well tolerated, where HSCs containing oncogenic mutations can overtake most of the hematopoietic system without transforming into leukemia (Jaiswal et al., 2014).”
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- Interpretationcitation
At the current time, there is substantial evidence that HSCs make regular and consistent contributions to hematopoiesis.
“At the current time, there is substantial evidence that HSCs make regular and consistent contributions to hematopoiesis, although further studies are needed to delineate the precise nature of these contributions, while accounting for limitations that exist for these different experimental approaches (Pucella et al., 2020).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Pucella et al., 2020 source
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- Interpretationnone given
Recent advances in genomic approaches are providing insights into the mechanisms that underlie key fate decisions in hematopoiesis.
“Recent advances in genomic approaches are providing insights into the mechanisms that underlie the key fate decisions in hematopoiesis.”
Quote in the paperSubstantial claim - Premisecitation
Cell barcoding approaches suggest that CMPs are a heterogeneous population of cells that have already made deterministic fate choices of lineage output.
“Moreover, cell barcoding approaches suggest that CMPs are a heterogeneous population of cells that have already made deterministic fate choices of lineage output (Perié et al., 2015).”
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- Premisecitation
Direct fluorescent labeling of mouse HSCs under steady state conditions illustrated a significant and continued contribution of HSCs to nearly all steady state hematopoiesis.
“Similarly, direct fluorescent labeling of mouse HSCs under steady state conditions illustrated a significant and continued contribution of HSCs to nearly all steady state hematopoiesis (Chapple et al., 2018; Sawai et al., 2016; Säwen et al., 2018).”
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Direct genetic barcoding in HSCs has resulted in similar findings.
“Direct genetic barcoding in HSCs has also resulted in similar findings (Rodriguez-Fraticelli et al., 2018).”
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- Interpretationcitation
Cells within the same compartment do not equally contribute to a particular lineage or to overall hematopoietic output.
“While barcoding efficiencies may complicate the interpretation of how different progenitors contribute to hematopoiesis, these observations appear to directly indicate that cells within the same compartment do not equally contribute to a particular lineage or to overall hematopoietic output.”
Quote in the paperSubstantial claim - Premisecitation
ChIP is not equally adept at measuring all interactions.
“While ChIP is not equally adept at measuring all interactions (Baranello et al., 2016; Teytelman et al., 2013), recent methods have overcome some of these limitations (Janssens et al., 2018; Skene and Henikoff, 2017; Skene et al., 2018; Zhu et al., 2019).”
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Single-cell measurements of transcriptional states, chromatin accessibility, and DNA methylation have provided a better understanding of heterogeneity in regulatory mechanisms during hematopoiesis.
“Single-cell measurements of transcriptional states, chromatin accessibility, and DNA methylation, have also provided a better understanding of the heterogeneity that exists in such regulatory mechanisms during hematopoiesis (Buenrostro et al., 2018; Cao et al., 2018; Ludwig et al., 2019b; Ulirsch et al., 2019).”
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Such approaches have contributed to understanding of the relationship between enhancer elements and the genes they regulate.
“Such approaches have contributed to our understanding of the relationship between enhancer elements and the genes they regulate (Giladi et al., 2018).”
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- Premisecitation
Combinatorial occupancy of chromatin by multiple master transcription factors has revealed regulatory networks important for hematopoiesis.
“For instance, the combinatorial occupancy of chromatin by multiple master TFs has revealed regulatory networks that are important for hematopoiesis (Beck et al., 2013; Schütte et al., 2016), as well as key regulatory elements necessary for HSC self-renewal (Bahr et al., 2018).”
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Even studies at a single locus can be illuminating, as exemplified by the identification of a hematopoietic-specific enhancer of MYC that is required by HSCs.
“Even studies at a single locus can be illuminating, as exemplified by the identification of a hematopoietic-specific enhancer of MYC that is required by HSCs (Bahr et al., 2018) (Figure 4B).”
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- Premisenone given
Despite decades of study, many distant regulatory elements of the α-globin gene cluster remained poorly characterized.
“Despite decades of study, many of the distant regulatory elements remained poorly characterized.”
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ATAC-seq and DNase hypersensitivity analyses have enabled important insights into alterations in regulatory regions with differentiation.
“Additionally, the assay for transposase-accessible chromatin using sequencing (ATAC-seq) and DNase hypersensitivity analyses have also enabled important insights into alterations in regulatory regions with differentiation (Klemm et al., 2019).”
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- Interpretationreasoning
Analyses of long-range chromatin interactions have revealed limitations of prior perturbation approaches.
“Such analyses have also revealed the limitations of prior perturbation approaches.”
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Targeting disruption of specific enhancer elements has demonstrated that many long-range regulatory elements additively enhance transcription.
“Furthermore, targeting disruption of specific enhancer elements has demonstrated that many of these long range regulatory elements additively enhance transcription (Hay et al., 2016) (Figure 4A).”
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- Premisereasoning
Single-cell profiling has illustrated how transcriptional dynamics change with time and state.
“Such single-cell profiling has illustrated how transcriptional dynamics change with time and state.”
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Combinatorial occupancy of chromatin by multiple master transcription factors has revealed key regulatory elements necessary for HSC self-renewal.
“For instance, the combinatorial occupancy of chromatin by multiple master TFs has revealed regulatory networks that are important for hematopoiesis (Beck et al., 2013; Schütte et al., 2016), as well as key regulatory elements necessary for HSC self-renewal (Bahr et al., 2018).”
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- Premisecitation
Improved genomic methods helped identify previously unappreciated roles for the transcription factor BCL11A in silencing fetal γ-globin genes via direct occupancy of the γ-globin-encoding HBG1/2 gene promoters.
“For instance, these methods have helped to identify previously unappreciated roles for the TF BCL11A in silencing the expression of the fetal γ-globin genes via the direct occupancy of the γ-globin-encoding HBG1/2 gene promoters (Liu et al., 2018).”
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- Premisenone given
With the use of proximity ligation, regulatory elements that control α-globin expression were discovered over 70 kb away.
“With the use of proximity ligation, regulatory elements that control α-globin expression were discovered over 70 kb away.”
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Recent methods have overcome some limitations of ChIP.
“While ChIP is not equally adept at measuring all interactions (Baranello et al., 2016; Teytelman et al., 2013), recent methods have overcome some of these limitations (Janssens et al., 2018; Skene and Henikoff, 2017; Skene et al., 2018; Zhu et al., 2019).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisenone given
Early methods used to identify key hematopoietic regulatory elements relied on regulatory elements being genetically nearby to the genes they regulated.
“Early methods used to identify key hematopoietic regulatory elements relied on regulatory elements being genetically nearby to the genes they regulated.”
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Within the last decade, hematopoietic regulatory elements have been identified that are quite distant from their associated genes, often separated by hundreds of kilobases.
“Within the last decade, however, hematopoietic regulatory elements have been identified that are quite distant from their associated genes, often separated by hundreds of kilobases (Amano et al., 2009; Mifsud et al., 2015; Sanyal et al., 2012; Schoenfelder et al., 2015).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationnone given
It is clear from studies of human variation that there is considerable inter-individual heterogeneity in hematopoiesis.
“However, it is clear from studies of human variation that there is considerable inter-individual heterogeneity in this process.”
Quote in the paperSubstantial claim - Premisereasoning
It has become possible to observe shifts in the epigenome and consequently the transcriptome that occur during continuous hematopoietic differentiation as separate lineages are favored.
“Furthermore, it has become possible to observe the shifts in the epigenome and consequently the transcriptome that occur during the continuous process of hematopoietic differentiation as separate lineages are favored.”
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Improved methods have revealed that many transcription factors can work together in connected regulatory networks to produce a unique phenotype and set of lineage fate choices.
“These improved methods have also revealed that many TFs can work together in connected regulatory networks to produce a unique phenotype and set of lineage fate choices.”
Quote in the paperNot a substantial claim - Interpretationreasoning
We are beginning to understand how chromatin conformation changes can bring distant regulatory elements into close proximity with the genes they control.
“We are beginning to understand how chromatin conformation changes can bring such distant regulatory elements into close proximity with the genes they control (Figure 4).”
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As genomic tools improve in throughput and accuracy, overlooked transcription factor interactions are now being identified.
“As genomic tools improve in their throughput and accuracy, overlooked TF interactions are now being identified.”
Quote in the paperSubstantial claim - Premisecitation
Scalable approaches using genome editing tools, such as CRISPR/Cas9, enable cis-regulatory elements to be dissected in cell lines and even in primary cell contexts.
“Scalable approaches using genome editing tools, such as CRISPR/Cas9, enable cis-regulatory elements to be dissected in cell lines and even in primary cell contexts (Fulco et al., 2016; Simeonov et al., 2017).”
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Proximity ligation approaches have contributed new insights into already well-studied genomic loci involved in hematopoiesis.
“These proximity ligation approaches have contributed new insights into already well-studied genomic loci involved in hematopoiesis.”
Quote in the paperSubstantial claim - Interpretationreasoning
Genomic advances have enabled researchers to more thoroughly understand the mechanisms that underlie hematopoietic cell fate decisions.
“Such genomic advances have enabled researchers to more thoroughly understand the mechanisms that underlie hematopoietic cell fate decisions.”
Quote in the paperSubstantial claim - Premisecitation
The α-globin gene cluster is carefully regulated to control transcription of the α-globin genes during erythroid maturation.
“One illustrative example is the α-globin gene cluster, which is carefully regulated to control the transcription of the α-globin genes during erythroid maturation (Sankaran and Weiss, 2015).”
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- Interpretationreasoning
By identifying long-range associations, the complexity of gene regulatory networks that coordinate hematopoietic differentiation can be more fully appreciated.
“By identifying such long-range associations, the complexity of the gene regulatory networks that coordinate hematopoietic differentiation can be more fully appreciated.”
Quote in the paperSubstantial claim - Premisecitation
Incorporating specific chromatin modifications and boundary elements at distant regulatory sites has created a more complete picture of the underlying regulation at the α-globin locus.
“Incorporating specific chromatin modifications and boundary elements at these distant regulatory sites has created a more complete picture of the underlying regulation at this locus (Brown et al., 2018; Hanssen et al., 2017; Oudelaar et al., 2017).”
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Proximity ligation methods have played an important role in identifying key interactions, such as promoter and enhancer associations.
“In the last decade, proximity ligation methods have played an important role in identifying these key interactions, such as promoter and enhancer associations (Kempfer and Pombo, 2020; Oudelaar et al., 2018; Quinodoz et al., 2018).”
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These methods enable epigenomic changes in primary hematopoietic cells to be deciphered in altered settings, such as aging.
“These methods also enable epigenomic changes in primary hematopoietic cells to be deciphered in altered settings, such as is observed with aging (Sun et al., 2014a).”
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- Premisecitation
Functional assessments of red blood cell trait-associated variants have revealed common mechanisms by which the activity of the master transcription factor GATA1 might be affected by genetic variants.
“For instance, functional assessments of red blood cell trait-associated variants have revealed common mechanisms by which the activity of the master TF GATA1 might be affected by genetic variants (Ulirsch et al., 2016).”
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- Premisecitation
The rate of new causal gene identification for rare blood disorders has been incredible in the past decade as a result of advances in massively parallel sequencing.
“The rate of new causal gene identification for such disorders, as with many other rare diseases, has been incredible in the past decade as a result of advances in massively parallel sequencing (Claussnitzer et al., 2020).”
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- Interpretationcitation
The coupling of genetic discoveries with single-cell genomic tools greatly increases potential to further refine understanding of hematopoiesis, as has been done in recent studies of congenital neutropenia.
“The coupling of these genetic discoveries with the single-cell genomic tools we have discussed in this review greatly increases our potential to further refine our understanding of hematopoiesis, as has been done elegantly in recent studies of congenital neutropenia (Muench et al., 2020).”
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- Premisecitation
The importance of polygenic variation on large-effect, monogenic variants has been clearly demonstrated for rare alleles, such as for BRCA1 and BRCA2 variants that predispose to breast cancer.
“The importance of polygenic variation on large-effect, monogenic variants has been clearly demonstrated for rare alleles, such as for the BRCA1 and BRCA2 variants that predispose to breast cancer (Fahed et al., 2019; Gallagher et al., 2020).”
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- cites Gallagher et al., 2020 source
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- Premisecitation
The ability to fine-map variants associated with blood cell traits and overlap these variants with accessible chromatin in hematopoietic progenitors has provided unprecedented insight into how genetic variation can influence a range of cell states in hematopoiesis.
“In addition, the ability to fine-map variants associated with blood cell traits and overlap these variants with accessible chromatin in hematopoietic progenitors has provided unprecedented insight into how genetic variation can influence a range of cell states in hematopoiesis (Ulirsch et al., 2019; Vuckovic et al., 2020).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Follow-up of GWAS for fetal hemoglobin revealed BCL11A to be a key regulator of fetal hemoglobin silencing.
“The follow up of these GWAS for HbF revealed BCL11A to be a key regulator of HbF silencing (Basak et al., 2015; Sankaran et al., 2008, 2009), a finding that has now led to further biological and therapeutic insights (Liu et al., 2018).”
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- cites Sankaran et al., 2008, 2009
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- Premisereasoning
A spectrum of allelic variation collectively affects the risk of having a blood disorder.
“Second, it is clear that a spectrum of allelic variation collectively affects the risk of having a blood disorder.”
Quote in the paperSubstantial claim - Interpretationreasoning
These associations suggest that human variation may modulate regulatory mechanisms across the full hematopoietic hierarchy.
“These associations suggest that human variation may modulate regulatory mechanisms across the full hematopoietic hierarchy (Figure 1) (Ulirsch et al., 2019).”
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- Premisecitation
Prior to the first genome-wide association studies into variation that impacts fetal hemoglobin levels, the regulators of fetal hemoglobin were poorly understood.
“For instance, prior to the first genome-wide association studies (GWAS) into variation that impacts fetal hemoglobin (HbF) levels - an important ameliorating factor for sickle cell disease and β-thalassemia - the regulators of HbF were poorly understood (Basak et al., 2020).”
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- Premisecitation
Through exome sequencing, rare individuals with Diamond-Blackfan anemia containing loss-of-function mutations in the hematopoietic master transcription factor GATA1 were identified.
“Through exome sequencing, rare individuals with DBA containing loss-of-function mutations in the hematopoietic master TF GATA1 were identified (Sankaran et al., 2012).”
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- Premisecitation
Alleles associated with monogenic blood disorders have begun to emerge from larger GWASs.
“First, alleles associated with monogenic blood disorders have begun to emerge from these larger GWASs.”
Quote in the paperSubstantial claim - Interpretationcitation
The emerging picture is that a spectrum of polygenic variation and large-effect monogenic variants collectively influence hematopoiesis to shape one's risk of having a blood disorder or altered hematopoiesis.
“The emerging picture is therefore that a spectrum of polygenic variation and large-effect monogenic variants collectively influence hematopoiesis to shape one’s risk of having a blood disorder or altered hematopoiesis (Vuckovic et al., 2020).”
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- Interpretationreasoning
With hundreds to thousands of loci now identified for each trait, blood cell-associated variants harbor considerable potential for gaining insights into the global mechanisms that underlie genetic variation altering hematopoiesis.
“With hundreds to thousands of loci now identified for each trait, such blood cell-associated variants also harbor considerable potential for gaining insights into the global mechanisms that underlie the genetic variation that alters hematopoiesis.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 18
- May combine two claims. 25
Classified as probably not a substantial claim.
Findingnone givenMethods to directly quantify HSC compartment size have remained elusive.
“However, methods to directly quantify HSC compartment size have remained elusive.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningFunctional interrogation of hematopoietic cell states can complement single cell transcriptomics and may reveal underlying biology that may be missed by scRNA-seq alone.
“Functional interrogation of hematopoietic cell states can complement single cell transcriptomics, and may reveal underlying biology that may be missed by scRNA-seq alone.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationPerturbing key master regulators while interrogating gene expression has revealed distinct transition points over the continuous transcriptomic landscape, suggesting punctuated transitions.
“Furthermore, with improved abilities to simultaneously interrogate gene expression, while perturbing key master regulators of this process, such as hematopoietic transcription factors (TFs), it has become clear that there are distinct transition points that occur over this continuous transcriptomic landscape, suggesting the presence of punctuated transitions (Giladi et al., 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Giladi et al., 2018 source
Not checked in the free run.
May combine two claims.
InterpretationcitationWhile hematopoiesis may be far more continuous than originally modeled, punctuated transitions across this continuous gene expression landscape may still exist and represent functionally distinct groups of cells.
“It must therefore be considered that while hematopoiesis may be far more of a continuous process than originally modeled, punctuated transitions across this continuous gene expression landscape may still exist, and represent functionally distinct groups of cells (Figure 1C) (Laurenti and Göttgens, 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Laurenti and Göttgens, 2018
Not checked in the free run.
May combine two claims.
InterpretationcitationGene expression alone may be insufficient to distinguish discrete cell populations and may miss other relevant aspects of biology.
“Thus, while the continuum model clearly addresses some of the oversimplifications of the classic model of hematopoiesis, gene expression alone may be insufficient to distinguish discrete cell populations and may miss other relevant aspects of biology (Olsson et al., 2016).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Olsson et al., 2016 source
Not checked in the free run.
Probably not a substantial claim: may not pass S4 (based).
Interpretationnone givenThe continuous nature of hematopoiesis is made possible by emergent outcomes of vast, interconnected regulatory networks that influence cell fates and lineage commitment.
“In part, this continuous nature of hematopoiesis is made possible by the emergent outcomes of vast, interconnected regulatory networks that influence cell fates and lineage commitment.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAs humans age, they typically experience an increase in total phenotypic HSC numbers as the cell pool grows with time.
“As humans age, they typically experience an increase in total phenotypic HSC numbers as the cell pool grows with time (de Haan and Van Zant, 1999; Pang et al., 2011; Sudo et al., 2000).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S1 (asserted).
PremisecitationLeveraging the high rate of mitochondrial mutations can track clonal dynamics within an unperturbed hematopoietic system in humans.
“In order to truly reflect cell behavior during steady state hematopoiesis, one promising alternative in humans involves leveraging the high rate of mitochondrial mutations to track clonal dynamics within an unperturbed hematopoietic system (Lareau et al., 2019; Ludwig et al., 2019a; Xu et al., 2019).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Lareau et al., 2019 source
Not checked in the free run.
- cites Ludwig et al., 2019a
Not checked in the free run.
- cites Xu et al., 2019
Not checked in the free run.
May combine two claims.
PremisecitationThe likelihood of CHIP increases with age, it appears in only a fraction of the population, and it increases the risk of cancer, cardiovascular disease, and other age-related morbidities.
“While the likelihood of CHIP increases with age, it appears in only a fraction of the population, and it increases the risk of cancer, cardiovascular disease, and other age-related morbidities (Bick et al., 2019a; Genovese et al., 2014; Jacobs et al., 2012; Jaiswal et al., 2014, 2017; Laurie et al., 2012; Xie et al., 2014).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisenone givenGenomic approaches include methods to identify TF binding events, chromatin modifications in specific genomic regions, and long-range chromatin interactions.
“As we discuss in this section, such approaches include methods to identify TF binding events, chromatin modifications in specific genomic regions, and long-range chromatin interactions.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationBarcodes produced through Cre-lox recombination in different hematopoietic cells confirmed a major replicative role of MPPs, while also demonstrating a consistent contribution of HSCs.
“However, barcodes produced through Cre-lox recombination in different hematopoietic cells confirmed a major replicative role of MPPs, while also demonstrating a consistent contribution of HSCs (Busch et al., 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Busch et al., 2015 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningThe resulting highly detailed and rich data has enabled large networks of interacting elements to be generated.
“The resulting highly detailed and rich data has enabled large networks of interacting elements to be generated”
Quote in the paperNot a substantial claimMay combine two claims.
Premisenone givenHuman genomic mutation rates tend to be low, which limits the resolution of clone tracking that can be achieved.
“While effective, human genomic mutation rates tend to be low, which limits the resolution of clone tracking that can be achieved.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationDuring steady state hematopoiesis, barcodes found within mature cells appeared to originate primarily from MPPs, suggesting that progenitors, rather than HSCs, carry most of the tissue-generation burden.
“During steady state hematopoiesis, barcodes found within mature cells appeared to originate primarily from MPPs, suggesting that progenitors, rather than HSCs, carry most of the tissue-generation burden.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sun et al., 2014b
Not checked in the free run.
May combine two claims.
PremisecitationRecent work has identified several genetic loci that confer risk of developing CHIP and myeloproliferative disorders with age, suggesting that alterations in fundamental cellular processes may promote clonal expansion.
“Moreover, recent work has identified several genetic loci that confer risk of developing CHIP and myeloproliferative disorders with age, suggesting that alterations in fundamental cellular processes may promote clonal expansion (Bao et al., 2019a; Bick et al., 2019b).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Bao et al., 2019a
Not checked in the free run.
- cites Bick et al., 2019b
Not checked in the free run.
May combine two claims.
PremisecitationAdvances in genomics over the past decade have enabled genotyping of large cohorts and sequencing of individuals using massively parallel methods, and have uncovered common variation that affects hematopoiesis and rare mutations that alter this process.
“Advances in genomics over the past decade have enabled the genotyping of large cohorts and the sequencing of individuals using massively parallel methods, such as exome or genome sequencing, and have uncovered common variation that affects hematopoiesis and also rare mutations that alter this process (Bao et al., 2019b).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bao et al., 2019b
Not checked in the free run.
May combine two claims.
InterpretationreasoningWhile environmental factors explain some of the inter-individual variation in hematopoiesis, genetic factors appear to have a considerable role, both in healthy individuals and in those affected by disease.
“While environmental factors undoubtedly explain some of this variation, genetic factors appear to have a considerable role, both in healthy individuals and in those affected by disease.”
Quote in the paperSubstantial claim- Rests on an assumption: Environmental factors explain some of the inter-individual variation in hematopoiesis.
May combine two claims.
PremisecitationPopulation-based genetic variation has largely been studied for blood cell traits, and over ten thousand loci have been defined across the allelic spectrum that explain inter-individual variation in such traits.
“Population-based genetic variation has largely been studied for blood cell traits, and over ten thousand loci have been defined across the allelic spectrum that explain inter-individual variation in such traits (Astle et al., 2016; Chen et al., 2020; Vuckovic et al., 2020).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.
Premisenone givenThe past decade has seen a dramatic increase in the use of genomic tools to decipher regulatory mechanisms, generating a wealth of rich genomic data.
“The past decade has seen a dramatic increase in the use of genomic tools to decipher regulatory mechanisms, which generate a wealth of rich genomic data.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationChIP-seq has been a valuable tool for accurately identifying transcription factor binding events.
“Historically, chromatin immunoprecipitation with sequencing (ChIP-seq) has been a valuable tool for accurately identifying TF binding events (Rhee and Pugh, 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Rhee and Pugh, 2011
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningUncoupling the pleiotropic roles of any transcription factor requires in-depth study beyond complete loss-of-function techniques commonly employed in the field.
“Uncoupling the pleiotropic roles of any TF requires in depth study, beyond the complete loss-of-function techniques that have commonly been employed in this field.”
Quote in the paperNot a substantial claim- Rests on an assumption: In most cases, the contribution of specific transcriptional regulatory elements to hematopoiesis remains unclear.
Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).
Interpretationnone givenAided by the genomics revolution, we are gaining a finer appreciation of the diverse and heterogeneous cell behaviors necessary to drive hematopoiesis.
“Aided by the genomics revolution, we are gaining a finer appreciation of the diverse and heterogeneous cell behaviors that are necessary to drive hematopoiesis.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationFunctional follow-up showed that the more common ribosomal gene mutations impair the translation of GATA1 mRNA and thus result in impaired erythropoiesis.
“Inspired by this discovery and through functional follow up, it was shown that the more common ribosomal gene mutations impair the translation of GATA1 mRNA and thus result in impaired erythropoiesis (Khajuria et al., 2018; Ludwig et al., 2014).”
Quote in the paperSubstantial claim0 of 2 sources checkedClassified as probably not a substantial claim. May combine two claims.
Premisenone givenStudies in human genetic variation have generally focused on identifying single variants significantly associated with a trait or disease through GWAS or disease-causal variants found in particular genes through sequencing-based approaches.
“Studies in this field have generally focused on identifying single variants that are significantly associated with a trait or disease of interest through GWAS or have focused on disease-causal variants found in particular genes through sequencing-based approaches (Figure 5).”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationInterrogation of specific loci identified through studies of population-based variation has uncovered key regulatory mechanisms, such as the role of specific GFI1B isoforms in megakaryopoiesis or the identification of a distinct CEBPA enhancer involved in the production of basophils.
“In other cases, the interrogation of specific loci identified through studies of population-based variation has uncovered key regulatory mechanisms, such as the role of specific GFI1B isoforms in megakaryopoiesis or the identification of a distinct CEBPA enhancer involved in the production of basophils (Guo et al., 2017; Polfus et al., 2016).”
Quote in the paperNot a substantial claim0 of 2 sources checkedClassified as probably not a substantial claim. May combine two claims.
InterpretationreasoningThese approaches have led to numerous important discoveries but have painted a dichotomized picture of human genetic variation affecting hematopoiesis, with rare variants having a big impact on disease and common genetic variants subtly tuning this process.
“These approaches have led to numerous important discoveries, but have also painted a dichotomized picture of the human genetic variation that affects hematopoiesis, with rare variants having a big impact on disease and common genetic variants subtly tuning this process.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.
Interpretationnone givenWe now understand a great deal of how the hematopoietic tissue behaves as a whole, but are just gaining the ability to understand how the combined functions of all cells in the tissue produce these emergent behaviors.
“We now understand a great deal of how the tissue behaves as a whole, but are just gaining the ability to understand how the combined functions of all cells in the tissue produce these emergent behaviors.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
InterpretationreasoningThe limitation that many barcoding approaches label only a fraction of hematopoietic stem and progenitor cells might significantly underrepresent the contributions of rare cell populations and the variation in differentiation dynamics.
“This limitation might significantly underrepresent the contributions of rare cell populations and the variation in differentiation dynamics.”
Quote in the paperSubstantial claim- Rests on an assumption: Many currently employed barcoding approaches are only efficient enough to label a fraction of hematopoietic stem and progenitor cells.
May combine two claims.
PremisecitationWhile clonal blood disorders or cancers are thought to primarily arise due to acquisition of somatic mutations in HSCs or other hematopoietic cells, inherited genetic variation can alter this risk significantly.
“For instance, while clonal blood disorders or cancers are thought to primarily arise due to the acquisition of somatic mutations in HSCs or in other hematopoietic cells, it is clear that inherited genetic variation can alter this risk significantly (Bao et al., 2019a; Bick et al., 2019b; Vijayakrishnan et al., 2018; Went et al., 2018).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Bao et al., 2019a
Not checked in the free run.
- cites Bick et al., 2019b
Not checked in the free run.
- cites Vijayakrishnan et al., 2018 source
Not checked in the free run.
May combine two claims.
PremisecitationSimilar discoveries have uncovered mutations in other hematopoietic transcription factors that alter homeostatic hematopoiesis and in some cases may increase the risk of developing blood cancers.
“Similar discoveries have uncovered mutations in other hematopoietic TFs that alter homeostatic hematopoiesis and that in some cases may increase the risk of developing blood cancers (Churpek and Bresnick, 2019; Kennedy and Shimamura, 2019).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Churpek and Bresnick, 2019
Not checked in the free run.
- cites Kennedy and Shimamura, 2019
Not checked in the free run.
Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based). May combine two claims.
InterpretationreasoningSuch flexibility might depend on the ability of the HSPC microenvironment to direct differentiation trajectories, and it is still unclear how much of this cell fate choice is intrinsic to the cells themselves.
“Such flexibility might depend on the ability of the HSPC microenvironment to direct the differentiation trajectories and it is still unclear how much of this cell fate choice is intrinsic to the cells themselves.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningThe genomic advances that have supported studies of human genetic variation have also constrained this field.
“The genomic advances that have supported studies of human genetic variation have also constrained this field.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
InterpretationreasoningThe possibility that older individuals can develop highly clonal HSPC compartments yet still have ostensibly normal hematopoiesis might indicate a significant degree of flexibility in the lineage output of HSPCs.
“This possibility might indicate a significant degree of flexibility in the lineage output of HSPCs.”
Quote in the paperNot a substantial claim- Rests on an assumption: Older individuals can develop HSPC compartments that are highly clonal and yet still continually regenerate functional tissue and have ostensibly normal hematopoiesis.
May combine two claims.
Premisenone givenScalable genotyping and sequencing technologies have empowered numerous population-based studies and enabled the discovery of rare genetic variation that underlies blood diseases.
“While scalable genotyping and sequencing technologies have empowered numerous population-based studies, these advances have also enabled the discovery of rare genetic variation that underlie blood diseases.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationDiamond-Blackfan anemia is a rare disorder characterized by impaired erythropoiesis; most patients have loss-of-function mutations in one of twenty-six distinct ribosome protein genes.
“For instance, Diamond-Blackfan anemia (DBA) is a rare disorder that is characterized by impaired erythropoiesis; most patients have loss-of-function mutations in one of twenty-six distinct ribosome protein genes (Ulirsch et al., 2018).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ulirsch et al., 2018 source
Not checked in the free run.
Classified as probably not a substantial claim.
Premisenone givenWhy mutations that affect ubiquitously expressed ribosomes cause a selective defect in erythropoiesis, and not defects in other hematopoietic lineages, was unknown.
“Why mutations that affect ubiquitously expressed ribosomes cause a selective defect in erythropoiesis, and not defects in other hematopoietic lineages, was unknown.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationThe size of the HSC compartment changes dramatically during development and considerably increases in the transition into adulthood.
“The size of the HSC compartment also changes dramatically during development, and considerably increases in the transition into adulthood (Ganuza et al., 2017; Werner et al., 2015).”
Quote in the paperNot a substantial claim0 of 2 sources checked
The paper relies on this without support.
In most cases, the contribution of specific transcriptional regulatory elements to hematopoiesis remains unclear.
“For instance, in most cases, the contribution of specific transcriptional regulatory elements to hematopoiesis remains unclear.”
The paper relies on this without support.
HSC compartment size estimates vary substantially.
“An important example is HSC compartment size, for which estimates vary substantially.”
The paper relies on this without support.
Many currently employed barcoding approaches are only efficient enough to label a fraction of hematopoietic stem and progenitor cells.
“Typically, many currently employed barcoding approaches are only efficient enough to label a fraction of hematopoietic stem and progenitor cells.”
The paper relies on this without support.
Older individuals can develop HSPC compartments that are highly clonal and yet still continually regenerate functional tissue and have ostensibly normal hematopoiesis.
“Older individuals can develop HSPC compartments that are highly clonal and yet still continually regenerate functional tissue and have ostensibly normal hematopoiesis.”
The paper relies on this without support.
Environmental factors explain some of the inter-individual variation in hematopoiesis.
“While environmental factors undoubtedly explain some of this variation, genetic factors appear to have a considerable role, both in healthy individuals and in those affected by disease.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Senescence of HSCs is the basis of immunosenescence.
“Senescence of HSCs is the basis of immunosenescence. Senescent HSC differentiate into various types of dysfunctional immune cells, driving immunosenescence.16”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [16]
The Clonal hematopoiesis section describes age-related changes in HSC numbers and clonal expansion, but does not link HSC senescence to immunosenescence. A search for immunosenescence and dysfunctional immune cells found no passage establishing that proposed mechanism; the Outstanding Questions section also notes that some older people retain ostensibly normal hematopoiesis. (LLM, conf=0.72)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Mouse parabiosis account conflicts with cited rat study
MinorThe text describes the Brecher and Cronkite experiment as connecting mice, but the cited reference identifies its subjects as rats.
“the circulatory systems of lethally irradiated mice and healthy mice were connected to demonstrate that the healthy hematopoietic tissue could rescue the lost function of the irradiated tissue (Brecher and Cronkite, 1951).”
“Brecher G, and Cronkite EP (1951). Post-radiation parabiosis and survival in rats.”
Sperm study cited as tracking hematopoietic clones
MinorThe sentence cites Wang et al. (2012) among studies tracking hematopoietic clonal dynamics, but the reference describes an analysis of human sperm.
“some studies have leveraged endogenous genomic DNA mutations to track hematopoietic clonal dynamics (Lee-Six et al., 2018; Osorio et al., 2018; Wang et al., 2012).”
“Wang J, Fan HC, Behr B, and Quake SR (2012). Genome-wide single-cell analysis of recombination activity and de novo mutation rates in human sperm.”
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The genetics of human hematopoiesis and its disruption in disease
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Self-citationA Critical Examination of the “Bad Luck” Explanation of Cancer Risk
Rozhok, A. I., Wahl, G. M., & DeGregori, J. V. (2015) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-15-0229 · Cited by 39 · see citing works
Single-Cell Computational Strategies for Lineage Reconstruction in Tissue Systems
Herring, C. A., Chen, B., McKinley, E. T., & Lau, K. S. (2018) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2018.01.023 · Cited by 35 · see citing works
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Inflammation and aging: signaling pathways and intervention therapies
Li, X., Li, C., Zhang, W., Wang, Y., Qian, P., & Huang, H. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01502-8 · Cited by 1,443 · see citing works
“Senescent HSC differentiate into various types of dysfunctional immune cells, driving immunosenescence.(16) Inflammation drives impaired selfrenewal activity and accelerates aging of HSCs.”
Background
- Authors
- Liggett, L. A., & Sankaran, V. G.
- Affiliations
- Broad Institute (US)
- Corresponding author
- Sankaran, Vijay G.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2020-09
- Volume
- 182
- Issue
- 6
- Pages
- 1384-1400
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC7508400
- OpenAlex
- W3087350907
- Semantic Scholar
- 594c47baa750b44cc5e9fee0ae8c742384266dcb
- Cited by
- 163
- References
- 207
- Citations by year
- 2026: 20 · 2025: 30 · 2024: 24 · 2023: 30 · 2022: 28 · 2021: 28 · 2020: 3
- FWCI
- 3.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01 DK103794, R01 HL146500, T32 HL066987)
- New York Stem Cell Foundation
- Leukemia and Lymphoma Society
- MPN Research Foundation
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- hematopoiesis, hematopoietic stem cells, lineage commitment, cell fate regulation, regulatory networks, genetic variation, cell tracking, histogenesis
- MeSH terms
- Human Genetics, Animals, Hematopoiesis, Hematopoietic Stem Cells, Homeostasis, Humans, Transcription Factors, Gene Expression Regulation, Developmental, Cell Lineage, Genomics
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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