Traba Silvio A, Bacigalupo Lucas, Fradin Daniella, Talon Irene, Heidenreich Ana C, Muraro Daniele, Garcia-Bernardo Jose, Gribben Christopher, Lugtu Fatima, Burgos Juan Ignacio, Romero Agustín, Chhatriwala Mariya, Pecci Adali, Vallier Ludovic, Rodríguez-Seguí Santiago A
Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), CONICET-Universidad de Buenos Aires, Ciudad Universitaria, C1428EGA Buenos Aires, Argentina.
Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1428EGA Buenos Aires, Argentina.
Development. 2025 Jun 1;152(11). doi: 10.1242/dev.204361. Epub 2025 May 27.
Understanding pancreatic development is instrumental to diabetes research and β-cell replacement therapies. Here, we investigate glucocorticoid receptor (GR) signaling during early pancreas development in mice and humans. Previous reports suggest that glucocorticoids do not play a significant role in mouse pancreas development before the second transition. In this study, we demonstrate that, under physiological conditions, the GR is selectively active in mouse pro-acinar and early endocrine cells from embryonic day 11.5, silenced in bipotent progenitors, and reactivated during endocrine commitment. In mouse pancreatic explants, ectopic GR activation globally promotes acinar fate. Surprisingly, GR activation in human in vitro-derived multipotent pancreatic progenitors steers lineage commitment toward a bipotent/endocrine trajectory and upregulates genes for which expression profiles resemble those of SOX9 and HES1 during human embryonic pancreatic bipotential and endocrine progenitor fate choice. Our combined epigenomic and single-cell transcriptomic analyses suggest that these newly identified marker genes may play important roles in human pancreas development. Taken together, our findings position the GR pathway as an endogenous developmental modulator of early-stage pancreatic progenitor cell differentiation and provide insights into the underlying transcriptional mechanisms involved.
了解胰腺发育对糖尿病研究和β细胞替代疗法至关重要。在此，我们研究小鼠和人类胰腺早期发育过程中的糖皮质激素受体（GR）信号传导。先前的报道表明，在第二次转变之前，糖皮质激素在小鼠胰腺发育中不发挥重要作用。在本研究中，我们证明，在生理条件下，GR在胚胎第11.5天起在小鼠前腺泡细胞和早期内分泌细胞中选择性激活，在双能祖细胞中沉默，并在内分泌细胞定向分化过程中重新激活。在小鼠胰腺外植体中，异位GR激活整体上促进腺泡命运。令人惊讶的是，在人源体外多能胰腺祖细胞中GR激活引导谱系定向分化为双能/内分泌轨迹，并上调在人类胚胎胰腺双能和内分泌祖细胞命运选择过程中表达谱类似于SOX9和HES1的基因。我们结合的表观基因组学和单细胞转录组学分析表明，这些新鉴定的标记基因可能在人类胰腺发育中发挥重要作用。综上所述，我们的研究结果将GR信号通路定位为早期胰腺祖细胞分化的内源性发育调节因子，并为所涉及的潜在转录机制提供了见解。
