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Micro-environmental sensing by bone marrow stroma identifies IL-6 and TGFβ1 as regulators of hematopoietic ageing

Author

Listed:
  • Simona Valletta

    (University of Oxford)

  • Alexander Thomas

    (University of Oxford)

  • Yiran Meng

    (University of Oxford)

  • Xiying Ren

    (University of Oxford)

  • Roy Drissen

    (University of Oxford)

  • Hilal Sengül

    (University of Oxford)

  • Cristina Genua

    (University of Oxford)

  • Claus Nerlov

    (University of Oxford)

Abstract

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.

Suggested Citation

  • Simona Valletta & Alexander Thomas & Yiran Meng & Xiying Ren & Roy Drissen & Hilal Sengül & Cristina Genua & Claus Nerlov, 2020. "Micro-environmental sensing by bone marrow stroma identifies IL-6 and TGFβ1 as regulators of hematopoietic ageing," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17942-7
    DOI: 10.1038/s41467-020-17942-7
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    Cited by:

    1. Pradeep Ramalingam & Michael C. Gutkin & Michael G. Poulos & Taylor Tillery & Chelsea Doughty & Agatha Winiarski & Ana G. Freire & Shahin Rafii & David Redmond & Jason M. Butler, 2023. "Restoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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