Micro-environmental sensing by bone marrow stroma identifies IL-6 and TGFβ1 as regulators of hematopoietic ageing
Open accessAbstract
Hematopoietic ageing involves declining erythropoiesis and lymphopoiesis, leading to frequent anaemia and decreased adaptive immunity. How intrinsic changes to the hematopoietic stem cells (HSCs), an altered microenvironment and systemic factors contribute to this process is not fully understood. Here we use bone marrow stromal cells as sensors of age-associated changes to the bone marrow microenvironment, and observe up-regulation of IL-6 and TGFβ signalling-induced gene expression in aged bone marrow stroma. Inhibition of TGFβ signalling leads to reversal of age-associated HSC platelet lineage bias, increased generation of lymphoid progenitors and rebalanced HSC lineage output in transplantation assays. In contrast, decreased erythropoiesis is not an intrinsic property of aged HSCs, but associated with decreased levels and functionality of erythroid progenitor populations, defects ameliorated by TGFβ-receptor and IL-6 inhibition, respectively. These results show that both HSC-intrinsic and -extrinsic mechanisms are involved in age-associated hematopoietic decline, and identify therapeutic targets that promote their reversal.
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Inflammatory cytokines, including TNF, TGF1β, IL-6 and IL-1β, have been found to be upregulated in aged bone marrow (HSC niche).
“Inflammatory cytokines, including TNF76, transforming growth factor-β1 (TGF1β)77, IL-6 (REF.78) and IL-1β (REF.79), have also been found to be upregulated in aged bone marrow (HSC niche).”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [77]
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- Authors
- Valletta, S., Thomas, A., Meng, Y., Ren, X., Drissen, R., Sengül, H., Di Genua, C., & Nerlov, C.
- Affiliations
- John Radcliffe Hospital (GB)
- Corresponding author
- Nerlov, Claus
- Venue
- Nature Communications
- Published
- 2020-08-14
- Volume
- 11
- Issue
- 1
- Pages
- 4075-4075
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7427787
- OpenAlex
- W3049244854
- Cited by
- 122
- References
- 65
- Citations by year
- 2026: 20 · 2025: 17 · 2024: 20 · 2023: 19 · 2022: 24 · 2021: 18 · 2020: 4
- FWCI
- 10.26
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- National Institute for Health and Care Research (131/030, 101/517)
- University of Oxford
- Blood Cancer UK (13064)
- Medical Research Council (MR/M00919X/1, MC_UU_12025, MR/T015055/1, #G0902418, MC_UU_12009, MC_UU_12009/7)
- Biotechnology and Biological Sciences Research Council (BB/M024350/1)
- 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
- mesenchymal stem cells, interleukin-6, TGF-beta signaling, hematopoietic stem cells, bone marrow microenvironment, erythropoiesis, lymphocyte development, erythroid progenitor cells, lymphoid progenitors, anemia, adaptive immunity
- MeSH terms
- Aging, Animals, Bone Marrow, Cell Cycle, Cells, Cultured, Disease Models, Animal, Erythropoiesis, Female, Gene Expression Regulation, Hematopoiesis, Hematopoietic Stem Cells, Membrane Proteins, Mice, Inbred C57BL, Signal Transduction, Erythroid Precursor Cells, Interleukin-6, Gene Expression Profiling, Myeloid Cells, Lymphopoiesis, Mice, Transforming Growth Factor beta1, Stem Cell Niche, Mesenchymal Stem Cells
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