Acute thrombocytopenia induces activation of long-term hematopoietic stem cells and leads to multipotent progenitor’s exhaustion

Long term hematopoietic stem cells (LT-HSCs) have a limited contribution to blood production during adulthood whereas multipotent progenitors (MPP) drive steady-state hematopoiesis. However, little is known about the role of the different HSC/progenitor populations under mild stress. We used an acute, specific platelet depletion model and found that, LT-HSCs (Lin- Sca-1+c-Kit+ CD48- CD150+) and MPP2 (Lin- Sca-1+c-Kit+ CD48+ CD150+), but not MPP3/4 (Lin-Sca-1+c-Kit+CD48+CD150-) proliferate in response to thrombocytopenia already after 12h. After transplantation into lethally irradiated mice the MPP2 gave rise to donor platelets significantly faster than LT-HSC or MPP3/4. Acute thrombocytopenia did not influence the repopulation capacity of LT-HSC and MPP3/4, but only led to a dramatic decrease of platelet production by MPP2. To further characterize these populations we found that CD41- LT-HSCs and CD41- MPP2 show faster and stronger activation of proliferation than their respective CD41+ cells. Activation of these particular cells is accompanied with the activation of Stat5 and Erk1,2 signaling pathways. These changes are not dependent on increased concentration of well-known thrombopoietic stimulators, including TPO and IL-6. Together, our data show that acute thrombocytopenia stimulates proliferation of CD41- LT-HSC and MPP2 which leads to the exhaustion of the progenitor pool.