Human endothelial colony-forming cells serve as trophic mediators for mesenchymal stem cell engraftment via paracrine signaling
Human endothelial colony-forming cells serve as trophic mediators for mesenchymal stem cell engraftment via paracrine signaling
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DOI：
10.1073/pnas.1405388111
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发表时间：
2014-07-15
影响因子：
11.1
通讯作者：
Melero-Martin, Juan M.
中科院分区：
文献类型：
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作者：
Lin, Ruei-Zeng;Moreno-Luna, Rafael;Melero-Martin, Juan M.
内皮集落形成细胞（ECFCs）是在外周血中循环的内皮前体。研究表明，人类ecfc具有强大的血管生成特性。然而，在体内，ecfc是否能够发挥营养功能来支持特定的干细胞在很大程度上仍然是未知的。在这里，我们试图确定人类ecfc是否可以在血液灌注建立之前作为旁分泌介质发挥作用。我们使用了两种人类间充质干细胞移植的异种移植模型，研究了ecfc的存在如何调节间充质干细胞的植入和体内再生能力。从白色脂肪组织和骨髓抽吸中分离出人间充质干细胞，在脐带血来源的ecfc存在或不存在的情况下，将其移植到免疫缺陷小鼠体内。MSC移植受ecfc衍生旁分泌因子通过血小板衍生生长因子BB (PDGF-BB)/血小板衍生生长因子受体(PDGFR)- β信号通路调控。共移植ECFCs通过减少pdgfr - β (+) MSCs的早期凋亡和保留其干细胞相关特性，包括继发移植物的再生能力，显著增强了MSC的植入。在没有ecfc的情况下，MSC移植可以忽略不计，在Tyrphostin AG1296（一种PDGFR激酶抑制剂）的存在下，MSC移植完全受损。此外，移植的间充质干细胞在体内表现出命运限制的潜力，脂肪组织来源的和骨髓来源的间充质干细胞分别沿着脂肪和成骨谱系进行排他性分化。这项研究表明，血源性ecfc可以作为旁分泌介质，通过PDGF-BB/ pdgfr - β信号通路调节MSCs的再生潜能。我们的数据表明系统地使用ecfc作为改善MSC移植的一种手段。
Endothelial colony-forming cells (ECFCs) are endothelial precursors that circulate in peripheral blood. Studies have demonstrated that human ECFCs have robust vasculogenic properties. However, whether ECFCs can exert trophic functions in support of specific stem cells in vivo remains largely unknown. Here, we sought to determine whether human ECFCs can function as paracrine mediators before the establishment of blood perfusion. We used two xenograft models of human mesenchymal stem cell (MSC) transplantation and studied how the presence of ECFCs modulates MSC engraftment and regenerative capacity in vivo. Human MSCs were isolated from white adipose tissue and bone marrow aspirates and were s.c. implanted into immunodeficient mice in the presence or absence of cord blood-derived ECFCs. MSC engraftment was regulated by ECFC-derived paracrine factors via platelet-derived growth factor BB (PDGF-BB)/platelet-derived growth factor receptor (PDGFR)-beta signaling. Cotransplanting ECFCs significantly enhanced MSC engraftment by reducing early apoptosis and preserving stemness-related properties of PDGFR-beta(+) MSCs, including the ability to repopulate secondary grafts. MSC engraftment was negligible in the absence of ECFCs and completely impaired in the presence of Tyrphostin AG1296, an inhibitor of PDGFR kinase. Additionally, transplanted MSCs displayed fate-restricted potential in vivo, with adipose tissue-derived and bone marrow-derived MSCs contributing exclusive differentiation along adipogenic and osteogenic lineages, respectively. This work demonstrates that blood-derived ECFCs can serve as paracrine mediators and regulate the regenerative potential of MSCs via PDGF-BB/PDGFR-beta signaling. Our data suggest the systematic use of ECFCs as a means to improve MSC transplantation.