利用间充质基质细胞功能化药物释放型人造骨架提高胰岛移植效果的相关研究

目前胰岛移植的长期临床疗效欠佳，关键原因在于移植后的胰岛环境差异以及免疫排斥反应等因素。我们的前期研究尝试利用药物释放型人造骨架模拟原位胰腺内的细胞外骨架生物学结构，为移植后的胰岛提供最优生存环境，取得了一定效果。国外临床预实验显示，间充质基质细胞可有助于遏制糖尿病人中胰岛功能的损失。我们拟建立间充质基质细胞的体外培养体系，并在人造骨架表面构建间充质基质细胞的单细胞层。单层细胞层形成后将大量产生细胞外骨架蛋白纤维，而这些蛋白纤维将大幅提高胰岛细胞的附着能力，并提高移植后胰岛细胞的存活率和临床疗效。此外，间充质基质细胞也可促使树突细胞转变为非炎症型，从而抑制移植后的免疫反应。我们将利用生物活性分子对间充质基质细胞的生物学功能进行干预，从而进一步促进它对于树突细胞的调控。本课题有望为进一步提高胰岛移植临床疗效，提供一个新的思路和技术手段。

The long term therapeutic effectiveness of islet transplantation for insulin-dependent patients remains far from being satisfactory. The primary reasons are the unfavorable in vivo environment for islets after transplantation and the immune rejection of the host. Based on our prior research, in this study we attempt to build an in situ environment with a high fidelity to its native one for transplanted islets using a drug-eluting electrospun scaffold. Furthermore, we fine-tuned the surface of the scaffold by engineering a monolayer of MSCs, which had been shown to inhibit the loss of islet functions in pre-clinical studies. We will establish a reliable system of harvesting, culturing and manipulating MSCs for therapeutic purposes. After forming a monolayer on the scaffold, MSCs will re-establish the native extracellular matrix (ECM) by producing protein fibers. This native ECM will greatly facilitate the adhesion of transplanted islets and translate into an increased survival rate and clinical performance of transplanted islets. In addition, MSCs can suppress the immune rejection after transplantation by inducing macrophages into an anti-inflammatory phenotype. We will manipulate the MSCs with bioactive molecules to fine tune its impact on macrophages. Our study will afford clinicians a novel strategy for enhancing the clinical effectiveness of islet transplantation.