间充质干细胞联合IGF-1C修饰的水凝胶治疗下肢缺血的分子影像学研究

The low cell engraftment after transplantation limits the successful application of stem cell therapy. Meanwhile, it is imperative to understand the dynamic processes of stem cell homing, migration, bio-distribution, proliferation, and differentiation in the same subject over time. In this proposal, we synthesize a bioactive hydrogel by immobilizing C-domain peptide of insulin-like growth factor 1 (IGF-1C) onto chitosan and hypothesize that the hydrogel could provide a favorable niche for human umbilical cord derived mesenchymal stem cells (hUC-MSC) and further enhance cell survival in mouse hindlimb ischemia model. Multimodality noninvasive imaging techniques with reporter gene approaches will be used to assess cell survival and therapeutic efficacy for restoration of hindlimb function. We are hopeful that this project would lead to (1) this hydrogel could increase cell viability by mimicking stem cell niches through paracrine effects further promote cell differentiation and increase limb function; (2) we could directly visualize the therapeutic effects of hydrogel with the advanced in vivo molecular imaging technique; (3) Moreover, molecular imaging technology utilized in this study made it possible to non-invasively monitor the transplanted stem cells and track the therapeutic mechanisms, such as cell apoptosis, metabolism, angiogenesis in vivo, which may significantly facilitate future stem cell therapy. Moreover, the tissue perfusion in the ischemic hindlimb could be quantitatively measured by the dynamic named near-infrared II (NIR-II) fluorescence imaging.

干细胞移植后在组织内的存活及驻留率较低，影响了干细胞的治疗效果。同时，干细胞移植后的监测以及作用机理的研究也是干细胞治疗的关键问题。本项目将应用人脐带来源的间充质干细胞（hUC-MSC)，联合偶联胰岛素样生长因子-1（IGF-1）C结构域（IGF-1C）的壳聚糖水凝胶，作为hUC-MSC的载体，移植治疗小鼠下肢缺血模型，结合多功能的报告基因系统标记移植的细胞，利用分子影像学方法，探讨细胞在体内的过程。期望通过本研究能够阐明： 1）偶联IGF-1C的水凝胶能够提供良好的细胞微环境，可以改善hUC-MSC在体内的存活，增强细胞多向分化能力，促进组织修复；2）报告基因技术，能够在体内捕获干细胞微环境中细胞-细胞相互作用及命运转归的直接影像学证据； 3）分子影像技术能较好的评价干细胞在组织内的凋亡、代谢、血管新生，近红外第二窗口成像（NIR-II）为示踪干细胞治疗后的血管新生提供了有力的评价方法。

干细胞移植后在组织内的存活及驻留率较低，影响了干细胞的治疗效果。同时，干细胞移植后的监测以及作用机理的研究也是干细胞治疗的关键问题。本项目应用壳聚糖水凝胶，偶联胰岛素样生长因子-1的C结构域（IGF-1C）作为间充质干细胞的载体，结合多功能的报告基因系统标记移植的细胞，利用分子影像技术监测干细胞在体内的存活、迁移、分化及器官功能改变，探讨在下肢缺血、皮肤损伤、肠炎、急性心肌梗死等疾病模型中干细胞的作用机理，根据不同的细胞移植方法对疾病模型的检测指标的改善情况及治疗效果，分子影像的方法为干细胞移植，提供了重要的评价手段，对干细胞在再生医学中的应用潜能提供了客观的认识。发表了通讯作者SCI收录论文22篇，其中2篇Biomaterials, 3篇Theranostics, 一篇ACS Nano, 一篇J Bio Chem。撰写了干细胞的英文专著，由Springer出版社出版。培养博士研究生3名, 硕士研究生6名。通过本项目的实施继续培养干细胞与分子影像的科研队伍。