Activin Enhances α- to β-Cell Transdifferentiation as a Source For β-Cells In Male FSTL3 Knockout Mice

Abstract

Diabetes results from inadequate β-cell number and/or function to control serum glucose concentrations so that replacement of lost β-cells could become a viable therapy for diabetes. In addition to embryonic stem cell sources for new β-cells, evidence for transdifferentiation/reprogramming of non-β-cells to functional β-cells is accumulating. In addition, de-differentiation of β-cells observed in diabetes and their subsequent conversion to α-cells raises the possibility that adult islet cell fate is malleable and controlled by local hormonal and/or environmental cues. We previously demonstrated that inactivation of the activin antagonist, follistatin-like 3 (FSTL3) resulted in β-cell expansion and improved glucose homeostasis in the absence of β-cell proliferation. We recently reported that activin directly suppressed expression of critical α-cell genes while increasing expression of β-cell genes, supporting the hypothesis that activin is one of the local hormones controlling islet cell fate and that increased activin signaling accelerates α- to β-cell transdifferentiation. We tested this hypothesis using Gluc-Cre/yellow fluorescent protein (YFP) α-cell lineage tracing technology combined with FSTL3 knockout (KO) mice to label α-cells with YFP. Flow cytometry was used to quantify unlabeled and labeled α- and β-cells. We found that Ins+/YFP+ cells were significantly increased in FSTL3 KO mice compared with wild type littermates. Labeled Ins+/YFP+ cells increased significantly with age in FSTL3 KO mice but not wild type littermates. Sorting results were substantiated by counting fluorescently labeled cells in pancreatic sections. Activin treatment of isolated islets significantly increased the number of YFP+/Ins+ cells. These results suggest that α- to β-cell transdifferentiation is influenced by activin signaling and may contribute substantially to β-cell mass.

Identification of a periodontal pathogen and bihormonal cells in pancreatic islets of humans and a mouse model of periodontitis

“…The literature reporting quantitative data on human bihormonal cells is limited 21,22 , and previous studies have not considered the possibility that bacterial pathogens may contribute to their emergence. Two possible means to induce conversion of α-cell to β-cell or β-cell to α-cell have been identified: (1) near complete ablation of β-cells using chemical agents 13,45,46 and (2) forced expression/deletion of βor α-cell specific transcription factors and/ or deletion of Dnmt1 or FOXO1 transcription factor in β-cells in mice [14][15][16]18,19 . We found that Pg/gingipain is not detected in mouse α-cells and at a low % in human α-cells, making it unlikely that Pg directly induces αto β-cell transdifferentiation.…”

“…The emergence of bihormonal cells in animal models has been reported following near complete destruction of β-cells (99% ablation) by chemical agent 13 or by forced expression/deletion of βor α-cell specific transcription factors [14][15][16][17] using conditional knockout and/or lineage tracing mice. Re-differentiation of α-cells from de-differentiated β-cells 18 also represents another means of developing intermediate/bihormonal cells.…”

How to make insulin-producing pancreatic β cells for diabetes treatment

“…Bramswig et al treated α cells with Adox, a histone methyltransferase inhibitor, and achieved partial conversion to insulin + cells (Bramswig et al, 2013). Recently it was observed that Activin enhanced α to β cell reprogramming (Brown et al, 2016), indicating that signaling regulation may contribute to α to β cell reprogramming.…”

Increased NKX6.1 expression and decreased ARX expression in alpha cells accompany reduced beta-cell volume in human subjects

“…It is well known that islet cells convert to the cells with other characteristics under various artificial conditions. Epigenomic manipulation is thought to provide a path to alpha- to beta-cell reprogramming 4 , and searches for materials that promote alpha- to beta-cell conversion are also progressing 5 – 7 . Genetic manipulations of transcription factors are also often conducted to induce transdifferentiation of islet cells.…”