Preservation of microvascular integrity and immunomodulatory property of prevascularized human mesenchymal stem cell sheets
Preservation of microvascular integrity and immunomodulatory property of prevascularized human mesenchymal stem cell sheets
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DOI：
10.1002/term.3167
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发表时间：
2021-01-28
影响因子：
3.3
通讯作者：
Zhao, Feng
中科院分区：
文献类型：
--
作者：
Jia, Wenkai;Sharma, Dhavan;Zhao, Feng
预血管化对于确保组织工程三维 (3D) 结构在移植后与周围宿主组织的活力、功能和成功整合至关重要。人间充质干细胞 (hMSC) 片可以通过与内皮细胞 (EC) 共培养来预血管化，然后进一步用作工程 3D 复杂组织的构建块。此外，hMSC 在体外预分化为组织特异性谱系已被证明可以促进移植物植入和再生。然而，目前尚不清楚预血管化的 hMSC 片在组织特异性分化后是否仍能保持其微血管完整性以及免疫调节特性。本研究的目的是研究分化线索对预血管化 hMSC 片的微血管结构、血管生成因子分泌和免疫原性反应的影响。结果表明，与ECs共培养后，hMSC片成功形成微血管网络，同时保持hMSCs的多谱系分化能力。下一步，成骨和脂肪诱导，破坏了预先形成的微血管结构并损害了 hMSC 的血管生成因子分泌能力。尽管如此，通过调整分化因子的浓度可以减轻这种影响。免疫功能正常的大鼠模型中的皮下移植表明，与未分化的预血管化 hMSC 片相比，成骨分化的预血管化 hMSC 片保留了其微血管结构和免疫调节特性。本研究表明，平衡且最佳的分化条件可以有效促进预血管化hMSC片的组织特异性预分化，同时保持其免疫调节和组织整合特性。
Prevascularization is essential to ensure the viability, functionality, and successful integration of tissue-engineered three-dimensional (3D) constructs with surrounding host tissues after transplantation. Human mesenchymal stem cell (hMSC) sheet can be prevascularized by coculturing with endothelial cells (ECs), and then be further used as building blocks for engineering 3D complex tissues. In addition, predifferentiation of hMSCs into a tissue-specific lineage in vitro has been proven to promote graft engraftment and regeneration. However, it is unclear if the prevascularized hMSC sheets can still maintain their microvascular integrity as well as the immune-regulatory properties after their tissue-specific differentiation. The objective of this study was to investigate the effects of differentiation cues on the microvascular structure, angiogenic factor secretion, and immunogenic responses of prevascularized hMSC sheets. The results showed that upon coculturing with ECs, hMSC sheets successfully formed microvascular network, while maintaining hMSCs' multi-lineage differentiation capability. The next step, osteogenic and adipogenic induction, damaged the preformed microvascular structures and compromised the angiogenic factor secretion ability of hMSCs. Nonetheless, this effect was mitigated by adjusting the concentration of differentiation factors. The subcutaneous transplantation in an immunocompetent rat model demonstrated that the osteogenic differentiated prevascularized hMSC sheet preserved its microvascular structure and immunomodulatory properties comparable to the undifferentiated prevascularized hMSC sheets. This study suggested that a balanced and optimal differentiation condition can effectively promote the tissue-specific predifferentiation of prevascularized hMSC sheet while maintaining its immunomodulatory and tissue integration properties.