Glucagon-producing α-cell transcriptional identity and reprogramming towards insulin production

Deep and comprehensive molecular analyses have started to pinpoint the genetic and epigenetic differences between α- and β-cells that could underlie the mechanisms defining their identity. The α-cell transcriptome is altered under different diabetic conditions, resulting in decreased expression of some α-cell-enriched genes alongside increased expression of some β-cell-enriched genes, but without reprogramming into insulin (INS)+ cells or activation of other key β-cell-specific genes. Multiple genetic and chemical methods have been used to reprogram mouse α-cells into INS-secreting cells in vivo, highlighting a difference in plasticity between embryonic and adult α-cells. Human α-cells have also been reprogrammed in vitro using PDX1 plus MAFA overexpression into INS-secreting cells that have reduced immunogenicity. Systematic molecular dissection of the mechanisms controlling α-cell reprogramming using an array of different in vitro and in vivo techniques will be necessary to develop efficient diabetes therapies. β-Cell replacement by in situ reprogramming of non-β-cells is a promising diabetes therapy. Following the observation that near-total β-cell ablation in adult mice triggers the reprogramming of pancreatic α-, δ-, and γ-cells into insulin (INS)-producing cells, recent studies are delving deep into the mechanisms controlling adult α-cell identity. Systematic analyses of the α-cell transcriptome and epigenome have started to pinpoint features that could be crucial for maintaining α-cell identity. Using different transgenic and chemical approaches, significant advances have been made in reprogramming α-cells in vivo into INS-secreting cells in mice. The recent reprogramming of human α-cells in vitro is an important step forward that must now be complemented with a comprehensive molecular dissection of the mechanisms controlling α-cell identity. β-Cell replacement by in situ reprogramming of non-β-cells is a promising diabetes therapy. Following the observation that near-total β-cell ablation in adult mice triggers the reprogramming of pancreatic α-, δ-, and γ-cells into insulin (INS)-producing cells, recent studies are delving deep into the mechanisms controlling adult α-cell identity. Systematic analyses of the α-cell transcriptome and epigenome have started to pinpoint features that could be crucial for maintaining α-cell identity. Using different transgenic and chemical approaches, significant advances have been made in reprogramming α-cells in vivo into INS-secreting cells in mice. The recent reprogramming of human α-cells in vitro is an important step forward that must now be complemented with a comprehensive molecular dissection of the mechanisms controlling α-cell identity.