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.
Highlights
Hematopoietic ageing involves declining erythropoiesis and lymphopoiesis, leading to frequent anaemia and decreased adaptive immunity
To determine whether decreased erythropoiesis is due to an intrinsic defect of aged hematopoietic stem cells (HSCs) we transplanted phenotypic long-term (LT-)HSCs (Lin−cKit+Sca-1+CD150+CD48−CD34−)[30,31] (Fig. 1b) from young (2–3-month-old) and aged mice (24-month-old) carrying the Vwf-tdTomato and Gata1-EGFP transgenes (VT/GE mice), which allow for accurate readout of erythrocytes, which are labelled by EGFP+, as well as platelets, which are both EGFP+ and tdTomato+14
Normalisation to platelet output, which is the lineage with the highest output from both young and aged HSCs, as well as single faterestricted HSCs14, showed that lymphoid output from aged HSCs was decreased, whereas myeloid and erythroid-lineage output did not decline relative to platelet output during ageing (Fig. 1h)
Summary
Hematopoietic ageing involves declining erythropoiesis and lymphopoiesis, leading to frequent anaemia and decreased adaptive immunity. 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. HSCs are heterogeneous in their lineage output, as demonstrated by single HSC transplantation[11,12,13,14], and the proportions of fate-restricted and lineage-biased HSCs change with age: HSCs with platelet and myeloid lineage bias become more prevalent, while the frequency of HSCs that produce lymphoid cell types decreases[15,16,17] The latter observation provides a cellular basis for the age-dependent decline in de novo production of naive B- and T-lymphocytes[18]. Quantitative studies measuring functional differences between young and aged HSCs have far not addressed if their intrinsic capacity for erythropoiesis is altered
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