MICA: Harnessing human Schwann cell-pancreatic progenitor cell interactions to optimise cell replacement therapy for type 1 diabetes

糖尿病目前影响全球近5亿人，其中约10%患有1型糖尿病（T1 D）。当胰腺中专门产生胰岛素的β细胞被免疫系统破坏时，就会发生T1 D。这些细胞可以在T1 D患者中被替换以改善血糖调节，但这种治疗是有限的，因为没有足够的β细胞供体。克服该问题的一个潜在策略是从容易获得的人干细胞群体产生大量用于移植的人β细胞。然而，目前从人类干细胞产生β细胞的方法依赖于从使用发育中的小鼠胰腺的研究中获得的信息：这些方法效率低下，并且不能产生功能性人类β细胞。这主要是由于调节小鼠和人类胰腺发育的信号通路的差异。尽管产生hiPSC衍生的辟田胞的体外方法旨在模拟辟田胞发育的复杂微环境，但我们对胰腺微环境对辟田胞发育的贡献的了解仍然不完整。因此，我使用新技术系统地分析了发育中的人类胰腺微环境，揭示了许旺细胞与内分泌祖细胞在空间上共同定位，它们可能有助于β细胞的特异性和成熟。因此，该奖学金项目将利用人类雪旺细胞-内分泌祖细胞相互作用来改善hIPSC衍生的胰腺祖细胞向β样细胞的分化，并使用1型糖尿病小鼠模型在体外和体内评估这些细胞的功能。从长远来看，从该项目中获得的知识将用于优化人类1型糖尿病治疗的细胞替代疗法。

Diabetes currently affects nearly half a billion people worldwide, approximately 10% of whom have type 1 diabetes (T1D). T1D occurs when the specialised insulin producing beta-cells in the pancreas are destroyed by the immune system. These cells can be replaced in people with T1D to improve blood glucose regulation, but this treatment is limited because there are insufficient beta-cell donors. One potential strategy for overcoming this problem is to generate large numbers of human beta-cells for transplantation from human stem cell populations, which are readily available. However, current methods for producing beta-cells from human stem cells rely on information obtained from studies using developing mouse pancreas: these methods are inefficient and do not produce functional human beta-cells. This is mainly due to the differences in the signalling pathways regulating development of mouse and human pancreas. Although the in vitro approach of generating hiPSC-derived beta cells is aimed at mimicking the complex microenvironment in which beta cells develop, our knowledge of the contribution of the pancreatic microenvironment to beta-cell development remains incomplete. I have therefore systematically profiled the developing human pancreas microenvironment using novel technologies to reveal that Schwann cells are spatially co-located with endocrine progenitors and they may contribute to beta-cell specification and maturation. This Fellowship project will therefore harness the human Schwann cell-endocrine progenitor interactions to improve differentiation of hIPSC-derived pancreatic progenitors to beta-like cells and assess the function of those cells in vitro and in vivo, using a mouse model of type 1 diabetes. The knowledge obtained from this project will, in the longer term, be used to optimise cell replacement therapy for type 1 diabetes treatment in humans.