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

Simona Valletta, Alexander Thomas, Yiran Meng, Xiying Ren, Roy Drissen, Hilal Sengül, Cristina Genua and Claus Nerlov ()
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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

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17942-7

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