Platelet Depletion Causes Rapid But Transient Activation Of Mouse Bone Marrow Long-Term Hematopoietic Stem Cells To Participate In Stress Thrombopoiesis

Hematopoietic stem cells (HSCs) are responsible for the production of various lineages of blood cells throughout life. To ensure the longevity of HSCs and prevent their premature exhaustion, a small population of HSCs termed long-term HSCs (LT-HSCs) is maintained in quiescence under homeostatic conditions. Whether LT-HSCs can exit quiescence rapidly in response to hematopoietic stress to replenish blood cells is not known, and thus was investigated in the present study in an acute but transient platelet depletion mouse model induced by intravenous injection of anti-GPIbα antibody. The results from our study show that in response to platelet depletion LT-HSCs can exit quiescence promptly and then proliferate rapidly to participate in stress thrombopoiesis probably via an alternative differentiation pathway. The mechanism by which platelet depletion causes LT-HSC activation is not due to a direct effect of the antibody on LT-HSCs or activation of platelets, but is attributed to a transient reduction of thrombopoietin (TPO) resulting from the acute depletion of platelets. However, the activated LT-HSCs return to quiescence when blood platelet counts are almost back to normal levels without compromising their function. These findings suggest that there is a very efficient and sensitive feedback regulatory circuitry between quiescent LT-HSCs and platelets, which allows LT-HSCs to directly and promptly respond to hematopoietic stress resulting from an acute loss of platelets. In this response, TPO may function as a switch that can rapidly turn on LT-HSCs to participate in stress thrombopoiesis.