肾素-血管紧张素系统介导的胰岛微环境对β细胞再分化的调控及机制

Type 2 diabetes is characterized by a steady decline in insulin secretion from pancreatic β cells. The recent breakthrough shows that the main cause of β cell dysfunction is dedifferentiation rather than apoptosis, which provides a novel strategy for type 2 diabetes prevention. The study obtained from lineage-tracing studies on β cell dysfunction demonstrates that adult murine β cells modify their differentiation state under conditions of physiological stress and assume a more progenitor-like state with multiple differentiation potential. β cells derive from facultative pancreatic progenitor cells mediated by several transcription factors, including Pdx-1, Ngn-3, MafA, and Nkx6.1. And the transcription factors Arx and Pax4, are master regulators of the α and β cell lineages differentiated from pro-α-cells, respectively. Pancreatic endothelium cells in embryonic islets release messages to promote the differentiation of embryonic pancreatic progenitor cells into β cells. The components of extracellular matrix derived from endothelium cells also modulate the differentiation. Our previous findings have shown that the shift of local renin-angiotensin system balance of pancreatic islet includes enhanced ACE-AngII-AT1R pathway or lack of ACE2-Ang (1-7) -Mas pathway. The imbalance exists in the type 2 diabetes and induces islet endothelial cell dysfunction and pancreatic islet microenvironment disorder, which furtherly affects the survival and function of beta cells. These data strongly indicate that a local RAS is involved in governing the functional maturation and differentiation. Thus, we suppose that in chronic metabolic stress the dysfunction of endothelium cells is the mainspring of the dedifferentiation via the abrogation of the RAS equivalence. We will alter the activation of ACE2/Ang(1-7)/mas axis via the administration of agonists or antagonists or gene knock and identify the β cell differentiation by genetic cell-lineage tracing approach to clarify the relationship between the dedifferentiation and intrinsic RAS in the β cell metabolic stress model. Pancreatic islet endothelium cells co-cultrure with islets of wild C57 mice or ACE2 knock out mice to observe the effect of redifferentiation. We will over express ACE2 mediated insulin promotor in β cells to remodel the glucose homeostasis in vivo.This study will find key transcription factors of β cells and key signaling molecules of islet endothelial cells. This study will provide further directions and a theoretical basis for future research and development to promote β-cell dedifferentiation and is bound to have a great application prospects.

最新研究显示代谢性应激（MS）时β细胞功能障碍主要源于FoxO1 等转录因子失活，β细胞去分化为具有多向分化潜能的内分泌祖细胞样细胞。本课题组前期研究表明MS时胰岛局部RAS通路失衡导致其介导的胰岛内皮细胞相关的微环境紊乱是β细胞功能障碍的关键因素，可通过上调ACE2-Ang（1-7）通路重塑胰岛RAS平衡所逆转。本研究拟采用ACE2基因敲除小鼠建立糖尿病前期 MS动物模型，以遗传追踪技术标记β细胞，聚焦于RAS介导的胰岛内皮细胞相关的微环境对β细胞分化状态的调控，应用基因芯片、共聚焦等技术筛查并检测β细胞去分化与再分化中关键转录因子和内皮细胞信号通路的表达变化，进而通过双调ACE2-Ang(1-7)通路探索以RAS为干预靶点重塑胰岛RAS平衡，促进去分化的β细胞再分化以逆转恢复其功能活性的作用价值及调控机制，为2型糖尿病防治中保护β细胞功能的治疗策略探寻新的研究方向。

近来的研究表明β细胞去分化是代谢应激状态下β细胞功能障碍的重要原因。去分化的β细胞具有多向分化潜能，可以再分化为其他内分泌细胞。本课题通过建立体内外代谢应激模型，以遗传追踪技术标记β细胞，聚焦于RAS对β细胞分化状态的调控，应用共聚焦等技术检测β细胞去分化与再分化中关键转录因子的表达变化。结果发现：(1)阻断血管紧张素II的作用可以有效地改善代谢应激下的胰岛素抵抗和β细胞功能障碍，减少β细胞去分化。（2）ACE2-Ang（1-7）-Mas信号上调改善胰岛微循环，减轻胰岛氧化应激，减少β细胞去分化。上述的研究结果提示，重塑Ras平衡可以促进去分化的β细胞再分化，恢复其功能活性。为2型糖尿病防治中保护β细胞功能的治疗策略探寻新的研究方向。