CD34 and EPCR coordinately enrich functional murine hematopoietic stem cells under normal and inflammatory conditions
Open accessAbstract
Hematopoiesis is dynamically regulated to maintain blood system function under nonhomeostatic conditions such as inflammation and injury. However, common surface marker and hematopoietic stem cell (HSC) reporter systems used for prospective enrichment of HSCs have been less rigorously tested in these contexts. Here, we use two surface markers, EPCR/CD201 and CD34, to re-analyze dynamic changes in the HSC-enriched phenotypic SLAM compartment in a mouse model of chronic interleukin (IL)-1 exposure. EPCR and CD34 coordinately identify four functionally and molecularly distinct compartments within the SLAM fraction, including an EPCR+/CD34- fraction whose long-term serial repopulating activity is only modestly impacted by chronic IL-1 exposure, relative to unfractionated SLAM cells. Notably, the other three fractions expand in frequency following IL-1 treatment and represent actively proliferating, lineage-primed cell states with limited long-term repopulating potential. Importantly, we find that the Fgd5-ZSGreen HSC reporter mouse enriches for molecularly and functionally intact HSCs regardless of IL-1 exposure. Together, our findings provide further evidence of dynamic heterogeneity within a commonly used HSC-enriched phenotypic compartment under stress conditions. Importantly, they also indicate that stringency of prospective isolation approaches can enhance interpretation of findings related to HSC function when studying models of hematopoietic stress.
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Increased PU.1 expression triggers enhanced activation of myeloid differentiation pathways in HSPC, leading to increased myeloid cell output, sometimes referred to as myeloid-biased hematopoiesis.
“Increased PU.1 expression in turn triggers enhanced activation of myeloid differentiation pathways in HSPC, leading to increased myeloid cell output, sometimes referred to as “myeloid-biased” hematopoiesis (Pietras et al., 2016; Rabe et al., 2020; Ahmed et al., 2022; Chavez et al., 2022).”
From PU.1 is required to restrain myelopoiesis during chronic inflammatory stress (2023) · cites this paper as Rabe et al., 2020
The Results sections on EPCR/CD34 enrichment and lineage priming (page unavailable) report that chronic IL-1 exposure expanded bone-marrow myeloid cells and increased expression of Spi1/Pu.1, a myeloid lineage determinant, in an HSC-enriched fraction. They do not establish that increased PU.1 itself activates myeloid differentiation pathways or causes the increased myeloid output. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe findings imply the existence of a braking mechanism that limits HSC cell cycle entry in response to chronic inflammatory stress.
“These findings imply the existence of a braking mechanism that limits HSC cell cycle entry in response to chronic inflammatory stress (Pietras et al., 2016; Rabe et al., 2020).”
From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as Rabe et al., 2020
IL-1β treatment for 20 d in mice models chronic inflammatory stress.
“isolated from the BM of mice treated with or without IL-1β for 20 d to model chronic inflammatory stress (Fig. 1 A; Pietras et al., 2016; Rabe et al., 2020).”
From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as Rabe et al., 2020
HSCLT-enriched SLAM cells overlap phenotypically with deeply quiescent CD49blo reserve HSCs and remain almost exclusively in a quiescent (G0) cell cycle state despite chronic IL-1 exposure.
“We previously showed that HSCLT-enriched SLAM cells (defined as LSK/Flk2−CD48−CD150+CD34−EPCR+; Fig. S1 E) overlap phenotypically with deeply quiescent CD49blo reserve HSCs (Zhao et al., 2019) and remain almost exclusively in a quiescent (G0) cell cycle state, despite chronic IL-1 exposure (Rabe et al., 2020).”
From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as Rabe et al., 2020
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- Authors
- Rabe, J. L., Hernandez, G., Chavez, J. S., Mills, T. S., Nerlov, C., & Pietras, E. M.
- Affiliations
- University of Colorado Anschutz (US)
- University of Oxford (GB)
- Corresponding author
- Pietras, Eric M.
- ORCID
- Venue
- Experimental Hematology
- Publisher
- Elsevier BV
- Published
- 2020-01
- Volume
- 81
- Pages
- 1-15.e6
- ISSN
- 0301-472X (ISSN-L)
- PMC
- PMC6938677
- OpenAlex
- W2995196097
- Cited by
- 49
- References
- 63
- Citations by year
- 2026: 9 · 2025: 3 · 2024: 5 · 2023: 5 · 2022: 13 · 2021: 10 · 2020: 4
- FWCI
- 4.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Experimental Hematology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Keywords
- hematopoietic stem cells, CD34, endothelial protein C receptor, SLAM family receptors, inflammation, HSC heterogeneity, HSC isolation, hematopoietic stress
- MeSH terms
- Endothelial Protein C Receptor, Animals, Hematopoiesis, Hematopoietic Stem Cells, Inflammation, Interleukin-1, Mice, Transgenic, Stress, Physiological, Antigens, CD34, Cell Proliferation, Mice
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