Glucose homeostasis depends on regulated insulin secretion from pancreatic β cells, which acquire their mature phenotype postnatally. The functional maturation of β cells is regulated by a combination of cell-autonomous and exogenous factors; the identity of the latter is mostly unknown. Here, we identify BMP4 as a critical component through which the pancreatic microenvironment regulates β cell function. By combining transgenic mouse models and human iPSCs, we show that BMP4 promotes the expression of core β cell genes and is required for proper insulin production and secretion. We identified pericytes as the primary pancreatic source of BMP4, which start producing this ligand midway through the postnatal period, at the age β cells mature. Overall, our findings show that the islet niche directly promotes β cell functional maturation through the timely production of BMP4. Our study highlights the need to recapitulate the physiological postnatal islet niche for generating fully functional stem-cell-derived β cells for cell replacement therapy for diabetes.

葡萄糖稳态取决于胰腺 β 细胞的胰岛素分泌调节，这些细胞在出生后获得成熟的表型。β细胞的功能成熟受细胞自主因素和外源因素共同调控；后者的身份大多不明。在这里，我们将 BMP4 确定为胰腺微环境调节 β 细胞功能的关键成分。通过将转基因小鼠模型和人类 iPSC 相结合，我们表明 BMP4 促进了核心 β 细胞基因的表达，并且是适当的胰岛素产生和分泌所必需的。我们将周细胞鉴定为 BMP4 的主要胰腺来源，在 β 细胞成熟时，它在出生后中期开始产生这种配体。全面的，我们的研究结果表明，胰岛生态位通过及时产生 BMP4 直接促进 β 细胞功能成熟。我们的研究强调需要概括出生后的生理胰岛生态位，以产生用于糖尿病细胞替代疗法的全功能干细胞衍生 β 细胞。