Decellularized Tissue Matrix Enhances Self-Assembly of Islet Organoids from Pluripotent Stem Cell Differentiation
Decellularized Tissue Matrix Enhances Self-Assembly of Islet Organoids from Pluripotent Stem Cell Differentiation
复制标题
DOI：
10.1021/acsbiomaterials.0c00088
复制
发表时间：
2020-07-01
影响因子：
5.8
通讯作者：
Jin, Sha
中科院分区：
文献类型：
--
作者：
Bi, Huanjing;Karanth, Soujanya S.;Jin, Sha
从干细胞中再生人类胰岛类器官仍然是一个重大挑战，因为我们对体外发育内分泌类器官所必需的线索知之甚少。在这项研究中，我们发现从去细胞化的大鼠胰腺细胞外基质（dpECM）制备的天然材料在诱导多能干细胞（iPSC）胰腺分化过程中诱导人类胰岛类器官的自组装。我们首次证明了在dpECM存在下形成的ipsc衍生的胰岛类器官能够分泌胰岛素和胰高血糖素，这两种主要的激素维持血糖稳态。类器官的特征表明，类器官包括所有主要的内分泌细胞类型，包括α、β、δ和胰腺多肽细胞，这些细胞被组装成类似于人类胰岛的组织结构。iPSCs在分化过程中暴露于dpECM导致关键胰腺转录因子（如PDX-1、MAFA和NKX6.1）的表达显著升高，并产生所有主要激素，包括胰岛素、胰高血糖素、生长抑素和来自干细胞衍生类器官的胰腺多肽。这项研究强调了天然的、具有生物活性的生物材料对于构建从干细胞中再生胰岛类器官至关重要的微环境的重要性。
Regenerating human islet organoids from stem cells remains a significant challenge because of our limited knowledge on cues essential for developing the endocrine organoids in vitro. In this study, we discovered that a natural material prepared from a decellularized rat pancreatic extracellular matrix (dpECM) induces the self-assembly of human islet organoids during induced pluripotent stem cell (iPSC) pancreatic differentiation. For the first time, we demonstrated that the iPSC-derived islet organoids formed in the presence of the dpECM are capable of glucose-responsive secretion of both insulin and glucagon, two major hormones that maintain blood glucose homeostasis. The characterization of the organoids revealed that the organoids consisted of all major endocrine cell types, including alpha, beta, delta, and pancreatic polypeptide cells, that were assembled into a tissue architecture similar to that of human islets. The exposure of iPSCs to the dpECM during differentiation resulted in considerably elevated expression of key pancreatic transcription factors such as PDX-1, MAFA, and NKX6.1 and the production of all major hormones, including insulin, glucagon, somatostatin, and pancreatic polypeptide from stem cell-derived organoids. This study highlights the importance of natural, bioactive biomaterials for building microenvironments crucial to regenerating islet organoids from stem cells.