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.
Aging, Animals, Bone Marrow, Cell Cycle, Cells, Cultured, Disease Models, Animal, Erythroid Precursor Cells, Erythropoiesis, Female, Gene Expression Profiling, Gene Expression Regulation, Hematopoiesis, Hematopoietic Stem Cells, Interleukin-6, Lymphopoiesis, Membrane Proteins, Mesenchymal Stem Cells, Mice, Mice, Inbred C57BL, Myeloid Cells, Signal Transduction, Stem Cell Niche, Transforming Growth Factor beta1