Thrombopoietin enhances hematopoietic stem and progenitor cell homing by impeding matrix metalloproteinase 9 expression

Abstract

Abstract We reported a novel function of recombinant human thrombopoietin (TPO) in increasing hematopoietic stem and progenitor cell (HSPC) homing to the bone marrow (BM). Single doses of TPO treatment to the recipients immediately after BM transplantation showed significantly improved homing of HSPCs to the BM, which subsequently resulted in enhanced short- and long-term engraftment of HSPCs in mice. We found that TPO could downregulate the expression and secretion of matrix metalloproteinase 9 in BM cells. As a result, SDF-1α level was increased in the BM niche. Blocking the interaction of SDF-1α and CXCR4 on HSPCs by using AMD3100 could significantly reverse the TPO-enhanced HSPC homing effect. More importantly, a single dose of TPO remarkably promoted human HSPC homing and subsequent engraftment to the BM of nonobese diabetic/severe combined immunodeficiency mice. We then performed a clinical trial to evaluate the effect of TPO treatment in patients receiving haploidentical BM and mobilized peripheral blood transplantation. Surprisingly, single doses of TPO treatment to patients followed by hematopoietic stem cell transplantation significantly improved platelet engraftment in the cohort of patients with severe aplastic anemia (SAA). The mean volume of platelet and red blood cell transfusion was remarkably reduced in the cohort of patients with SAA or hematological malignancies receiving TPO treatment. Thus, our data provide a simple, feasible, and efficient approach to improve clinical outcomes in patients with allogenic hematopoietic stem cell transplantation. The clinical trial was registered in the Chinese Clinical Trial Registry website (www.chictr.org.cn) as ChiCTR-OIN-1701083. Lessons learned • Thrombopoietin (TPO) administration on the day of transplantation was shown to be safe and beneficial for those patients in a haploidentical hematopoietic stem cell transplantation setting, especially for the patients with severe aplastic anemia.• TPO administration on the day of transplantation significantly reduced the number of platelet units and red blood cell units transfused for those patients with severe aplastic anemia or hematologic malignancies receiving hematopoietic stem cell transplantation.  Significance statementThis article reports a novel function of recombinant human thrombopoietin (TPO) in increasing hematopoietic stem and progenitor cell (HSPC) homing to the bone marrow (BM), which subsequently resulted in enhanced long-term engraftment of HSPCs in mice. Notably, TPO treatment to patients followed by hematopoietic stem cell transplantation improved platelet engraftment outcomes, especially in patients with severe aplastic anemia. To the best of authors’ knowledge, the results of this study are innovative and might represent a valuable and rapid pathway for improving HSPC homing to the BM and the hematopoietic repopulation efficiency in patients.