Exogenous Lactogenic Signaling Stimulates Beta Cell Replication In Vivo and In Vitro

Abstract

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.

Beta-cell compensation and gestational diabetes

“…This effect contributes to the enlargement of islets (islet hypertrophy) secondary to increased numbers of β-cells per islet (β-cell hyperplasia), accounting for enhanced glucose-stimulated insulin secretion from maternal islets. This finding is recapitulated in rats and mice during pregnancy and mice with gestational hormone-elicited pseudopregnancy ( 43 , 47 , 48 , 49 ). It follows that β-cell mass expansion, characterized by increased β-cell replication, constitutes a major mechanism of β-cell compensation for pregnancy.…”

“…Millette et al. developed a mouse model with pseudopregnancy through subcutaneous administration of estrogen and placental lactogen, showing that pseudopregnant mice are associated with a significant induction in β-cell proliferation without changes in β-cell size within islets ( 49 ). Thus, it remains an open question as to whether β-cells undergo hypertrophy and what is the underlying physiology of β-cell hypertrophy.…”

Systematic Bayesian Posterior Analysis Guided by Kullback-Leibler Divergence Facilitates Hypothesis Formation

“…While there has been significant research investigating SOCS’ role in the canonical JAK-STAT pathway, as well as the role of SOCS in PRL-mediated JAK2-STAT5 signaling, no observations of SOCS dynamics for our exact system of study exist (Chong et al, 2001; Croker et al, 2008; Jiao et al, 2013; Millette et al, 2022; Ram and Waxman, 1999; Rieck et al, 2009; Rønn et al, 2002; Ye and Driver, 2016). Thus, determining the dynamics of SOCS in response to PRL is an open challenge in pancreatic beta cell biology.…”

“…We demonstrate our approach on a biologically relevant model of pancreatic beta cell signaling. Because a decrease in beta cell mass is a hallmark of Type 2 diabetes, previous research has set out to understand signaling pathways that govern beta cell proliferation to design novel approaches to expand functional beta cell mass (Aguayo-Mazzucato and Bonner-Weir, 2018; Brelje et al, 2004; Fujinaka et al, 2007; Jiao et al, 2013; Millette et al, 2022; Rieck et al, 2009; Rønn et al, 2002; Salazar-Petres and Sferruzzi-Perri, 2022). Pregnancy has been a key model system to understand beta cell proliferation.…”

The Pancreatic Beta Cell: Editorial

“…Beta cell hyperplasia during pregnancy is well known, but beta cell effectors are not yet fully understood. Millete and collaborators [ 11 ] described the novel in vivo and in vitro models of pseudopregnancy using a hormone cocktail, which could recapitulate the hyperplasic response seen during pregnancy.…”