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

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 TGF beta signalling-induced gene expression in aged bone marrow stroma. Inhibition of TGF beta 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 TGF beta -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. Ageing of the haematopoietic system is accompanied by declining erythropoiesis and lymphopoiesis. Here the authors uncover upregulated IL-6 and TGF beta signalling in aged bone marrow stroma; inhibition of these signals reverses age-related haematopoietic defects, re-balancing haematopoietic stem cell lineage output.