Department of Cardiac Surgery, Boston Children's Hospital, and Department of Surgery, Harvard Medical School, Boston, MA 02115;
Center for Vascular Biology, Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA 02215;
Proc Natl Acad Sci U S A. 2014 Jul 15;111(28):10137-42. doi: 10.1073/pnas.1405388111. Epub 2014 Jun 30.
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)-β signaling. Cotransplanting ECFCs significantly enhanced MSC engraftment by reducing early apoptosis and preserving stemness-related properties of PDGFR-β(+) 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-β signaling. Our data suggest the systematic use of ECFCs as a means to improve MSC transplantation.
内皮祖细胞（ECFCs）是循环于外周血中的内皮前体细胞。研究表明，人 ECFCs 具有强大的血管生成特性。然而，ECFCs 是否能在体内发挥营养作用以支持特定的干细胞，在很大程度上仍然未知。在这里，我们试图确定人 ECFCs 是否能在建立血液灌注之前作为旁分泌介质发挥作用。我们使用了两种人间充质干细胞（MSC）移植的异种移植模型，并研究了 ECFCs 的存在如何调节 MSC 体内定植和再生能力。人 MSCs 从白色脂肪组织和骨髓抽吸物中分离出来，并在存在或不存在脐带来源的 ECFCs 的情况下，皮下植入免疫缺陷小鼠体内。MSC 的植入受 ECFC 衍生的旁分泌因子调节，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信号转导。共移植 ECFCs 通过减少早期凋亡和保持 PDGFR-β（+）MSCs 的干细胞相关特性，包括再种植次级移植物的能力，显著增强了 MSC 的植入。在没有 ECFCs 的情况下，MSC 的植入可以忽略不计，而在 PDGFR 激酶抑制剂 Tyrphostin AG1296 的存在下，MSC 的植入则完全受损。此外，移植的 MSCs 在体内表现出命运受限的潜力，脂肪组织来源的和骨髓来源的 MSCs 分别沿着脂肪生成和成骨谱系进行独特的分化。这项工作表明，血液来源的 ECFCs 可以作为旁分泌介质，并通过 PDGF-BB/PDGFR-β 信号转导调节 MSC 的再生潜力。我们的数据表明，系统地使用 ECFCs 作为一种改善 MSC 移植的方法。
