Thrombopoietin enhances hematopoietic stem and progenitor cell homing by impeding matrix metalloproteinase 9 expression
Thrombopoietin enhances hematopoietic stem and progenitor cell homing by impeding matrix metalloproteinase 9 expression
复制标题
血小板生成素通过阻止基质金属蛋白酶 9 表达增强造血干细胞和祖细胞归巢
DOI：
10.1002/sctm.19-0220
复制
发表时间：
2020-06-01
影响因子：
6
通讯作者：
Pei, Xuetao
中科院分区：
文献类型：
--
作者：
Liu, Yiming;Ding, Li;Pei, Xuetao
我们报道了重组人血小板生成素（TPO）在促进造血干细胞和祖细胞（HSPC）归巢至骨髓（BM）中的新功能。在骨髓移植后立即对受体进行单剂量TPO治疗显示HSPC向骨髓的归巢显著改善，这随后导致小鼠中HSPC的短期和长期植入增强。我们发现TPO可下调骨髓细胞基质金属蛋白酶9的表达和分泌。结果，骨髓小生境中SDF-1 α水平增加。通过使用AMD 3100阻断SDF-1 α和CXCR 4在HSPC上的相互作用可以显著逆转TPO增强的HSPC归巢效应。更重要的是，TPO单次给药显著促进人HSPC归巢和随后植入非肥胖糖尿病/重度联合免疫缺陷小鼠的BM。然后，我们进行了一项临床试验，以评估TPO治疗接受半相合骨髓和动员外周血移植的患者的效果。令人惊讶的是，对患者进行单剂量TPO治疗，随后进行造血干细胞移植，显著改善了患有重度再生障碍性贫血（SAA）的患者队列中的血小板植入。血小板和红细胞输注的平均量显着减少的SAA或血液恶性肿瘤患者接受TPO治疗的队列。因此，我们的数据提供了一个简单，可行，有效的方法来改善异基因造血干细胞移植患者的临床结果。
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-1 alpha level was increased in the BM niche. Blocking the interaction of SDF-1 alpha 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.