Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Center for Endocrinology, Diabetes and Metabolism, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
Biomolecules. 2022 Jan 26;12(2):215. doi: 10.3390/biom12020215.
As patients recently diagnosed with T1D and patients with T2D have residual beta cell mass, there is considerable effort in beta cell biology to understand the mechanisms that drive beta cell regeneration as a potential cellular therapy for expanding patients' residual beta cell population. Both mouse and human studies have established that beta cell mass expansion occurs rapidly during pregnancy. To investigate the mechanisms of beta cell mass expansion during pregnancy, we developed a novel in vivo and in vitro models of pseudopregnancy. Our models demonstrate that pseudopregnancy promotes beta cell mass expansion in parous mice, and this expansion is driven by beta cell proliferation rather than hypertrophy. Importantly, estrogen, progesterone, and placental lactogen induce STAT5A signaling in the pseudopregnancy model, demonstrating that this model successfully recapitulates pregnancy-induced beta cell replication. We then created an in vitro model of pseudopregnancy and found that the combination of estrogen and placental lactogen induced beta cell replication in human islets and rat insulinoma cells. Therefore, beta cells both in vitro and in vivo increase proliferation when subjected to the pseudopregnancy cocktail compared to groups treated with estradiol or placental lactogen alone. The pseudopregnancy models described here may help inform novel methods of inducing beta cell replication in patients with diabetes.
由于最近被诊断出患有 T1D 的患者和 T2D 患者仍有β细胞群，因此在β细胞生物学方面进行了大量研究，以了解驱动β细胞再生的机制，β细胞再生作为扩大患者残留β细胞群的潜在细胞治疗方法。 小鼠和人类的研究都已经证实，β细胞质量在怀孕期间迅速扩大。为了研究怀孕期间β细胞质量扩大的机制，我们开发了一种新的体内和体外假孕模型。我们的模型表明，假孕会促进已生育小鼠的β细胞质量扩大，而这种扩大是由β细胞增殖而非肥大驱动的。重要的是，雌激素、孕激素和胎盘催乳素在假孕模型中诱导 STAT5A 信号，表明该模型成功地再现了妊娠诱导的β细胞复制。然后，我们创建了一个体外假孕模型，发现雌激素和胎盘催乳素的组合可诱导人胰岛和大鼠胰岛素瘤细胞中的β细胞复制。因此，与单独用雌二醇或胎盘催乳素处理的组相比，β细胞在体外和体内受到假孕鸡尾酒的刺激时，增殖增加。 这里描述的假孕模型可能有助于为糖尿病患者提供诱导β细胞复制的新方法。
