KLF2+ stemness maintains human mesenchymal stem cells in bone regeneration
KLF2+ stemness maintains human mesenchymal stem cells in bone regeneration
复制标题
KLF2( ) 干性维持人间充质干细胞的骨再生。
DOI：
10.1002/stem.3120
复制
发表时间：
2019-12-14
期刊：
影响因子：
5.2
通讯作者：
Wang, Huiming
中科院分区：
文献类型：
--
作者：
Zhou, Ying;Liu, Chao;Wang, Huiming
间充质干细胞(MSCs)是一种未分化的干细胞，具有干细胞的特性，具有向包括成骨细胞在内的多个谱系分化的潜能，在骨组织工程领域引起了极大的关注。与MSCs的异质性相一致的是，各种表面标记已经被使用。然而，目前还不清楚哪些MSCs的标志物最适合体外细胞扩增和后来体内骨再生。Kruppel-like factor2(KLF2)是衡量人骨髓间充质干细胞(HMSCs)干性的重要指标，早期血管形成对骨再生也具有重要意义，我们将KLF2作为一种新的MSCs体外标记物，研究了KLF2(+)MSCs与内皮细胞(ECs)之间的血管生成和成骨作用。我们发现hMSCs和人脐静脉内皮细胞(HUVECs)之间存在协同作用，KLF2(+)保持干细胞干性的hMSCs最初促进HUVECs的血管生成，进而更有效地刺激hMSCs的成骨。事实上，KLF2(+)hMSCs最初会分泌血管生成因子，然后部分细胞通过PDGF-BB/PDGFR-β信号通路分化为周细胞，从而促进血管形成。成熟的人脐静脉内皮细胞通过上调血管内皮生长因子，协同促进KLF2(+)hMSCs的成骨。细胞负载的明胶甲基丙烯酸酯(GelMA)水凝胶的三维共培养模型进一步证实了这些结果。这项研究为hMSCs和HUVECs之间的茎定向协同作用提供了深入的见解，我们的结果将对进一步的策略产生深远的影响，包括KLF2(+)hMSC/HUVEC负载GelMA水凝胶在血管网络生物工程和骨再生中的应用。
Mesenchymal stem cells (MSCs), which are undifferentiated stem cells with the property of stemness and the potential to differentiate into multiple lineages, including osteoblasts, have attracted a great deal of attention in bone tissue engineering. Consistent with the heterogeneity of MSCs, various surface markers have been used. However, it is still unclear which markers of MSCs are best for cell amplification in vitro and later bone regeneration in vivo. Kruppel-like Factor 2 (KLF2) is an important indicator of the stemness of human MSCs (hMSCs) and as early vascularization is also critical for bone regeneration, we used KLF2 as a novel in vitro marker for MSCs and investigated the angiogenesis and osteogenesis between KLF2(+) MSCs and endothelial cells (ECs). We found a synergistic interaction between hMSCs and human umbilical vein ECs (HUVECs) in that KLF2(+) stemness-maintained hMSCs initially promoted the angiogenesis of HUVECs, which in turn more efficiently stimulated the osteogenesis of hMSCs. In fact, KLF2(+) hMSCs secreted angiogenic factors initially, with some of the cells then differentiating into pericytes through the PDGF-BB/PDGFR-beta signaling pathway, which improved blood vessel formation. The matured HUVECs in turn synergistically enhanced the osteogenesis of KLF2(+) hMSCs through upregulated vascular endothelial growth factor. A three-dimensional coculture model using cell-laden gelatin methacrylate (GelMA) hydrogel further confirmed these results. This study provides insight into the stemness-directed synergistic interaction between hMSCs and HUVECs, and our results will have a profound impact on further strategies involving the application of KLF2(+) hMSC/HUVEC-laden GelMA hydrogel in vascular network bioengineering and bone regeneration.