血管紧张素Ⅱ受体2型对于人类胎儿胰腺祖细胞发育为胰岛样细胞簇的至关重要作用及其用于移植的潜能

Local renin-angiotensin systems (RASs) regulate the differentiation of tissue progenitors. However, it is not known whether such systems can regulate the development of pancreatic progenitor cells (PPCs). To address this issue, we characterized the expression profile of major RAS components in human fetal PPC preparations and examined their effects on the differentiation of PPCs into functional isletlike cell clusters (ICCs). We found that expression of RAS components was highly regulated throughout PPC differentiation and that locally generated angiotensin II (Ang II) maintained PPC growth and differentiation via Ang II type 1 and type 2 (AT 1 and AT 2) receptors. In addition, we observed colocalization of AT 2 receptors with critical β-cell phenotype markers in PPCs/ICCs, as well as AT 2 receptor upregulation during differentiation, suggesting that these receptors may regulate β-cell development. In fact, we found that AT 2, but not AT 1, receptor was a key mediator of Ang II-induced upregulation of transcription factors important in β-cell development. Furthermore, lentivirusmediated knockdown of AT 2 receptor suppressed the expression of these transcription factors in ICCs. Transplantation of AT 2 receptor-depleted ICCs into immune-privileged diabetic mice failed to ameliorate hyperglycemia, implying that AT 2 receptors are indispensable during ICC maturation in vivo. These data strongly indicate that a local RAS is involved in governing the functional maturation of pancreatic progenitors toward the endocrine lineage.