Abstract
Direct lineage conversion of adult cells is a promising approach for regenerative medicine. A major challenge of lineage conversion is to generate specific cell subtypes. The pancreatic islets contain three major hormone-secreting endocrine subtypes: insulin(+) β-cells, glucagon(+) α-cells, and somatostatin(+) δ-cells. We previously reported that a combination of three transcription factors, Ngn3, Mafa, and Pdx1, directly reprograms pancreatic acinar cells to β-cells. We now show that acinar cells can be converted to δ-like and α-like cells by Ngn3 and Ngn3+Mafa respectively. Thus, three major islet endocrine subtypes can be derived by acinar reprogramming. Ngn3 promotes establishment of a generic endocrine state in acinar cells, and also promotes δ-specification in the absence of other factors. δ-specification is in turn suppressed by Mafa and Pdx1 during α- and β-cell induction. These studies identify a set of defined factors whose combinatorial actions reprogram acinar cells to distinct islet endocrine subtypes in vivo. DOI: http://dx.doi.org/10.7554/eLife.01846.001.
Highlights
Cellular reprogramming is a rapidly expanding area of regenerative medicine
We have previously reported that pancreatic acinar cells can be converted to insulin+ β-like cells by the combined activity of three reprogramming factors: Ngn3, Mafa, and Pdx1, referred to as M3 factors (Zhou et al, 2008)
Developmental biology and stem cells pancreas, which targets acinar cells (Figure 1A, Figure 1—figure supplement 1), we examined the role of individual M3 factors in endocrine reprogramming
Summary
Cellular reprogramming is a rapidly expanding area of regenerative medicine. With suitable reprogramming factors, adult cells can be instructively converted to induced pluripotent stem cells (pluripotent reprogramming) or other types of adult cells (lineage reprogramming) (Gurdon and Melton, 2008; Graf and Enver, 2009). Induced pluripotent stem cells (iPS) can be differentiated into many cell types in the body. Lineage conversion between adult cell types offers a promising alternative, directly producing defined cell types in vitro or even in vivo that may be used for disease modeling and cellular therapies (Zhou and Melton, 2008; Vierbuchen and Wernig, 2011). Recent examples of lineage reprogramming include the conversion of pre-B cells to macrophages, pancreatic acinar, α-cells, and gut cells to insulin-secreting β-cells, cardiac fibroblasts to cardiomyocyte-like cells, amniotic cells to endothelial cells, and skin fibroblasts to neurons, oligodendrocytes, neural precursors, or blood progenitors (Xie et al, 2004; Zhou et al, 2008; Ieda et al, 2010; Szabo et al, 2010; Thorel et al, 2010; Vierbuchen et al, 2010; Caiazzo et al, 2011; Yang et al, 2011; Ginsberg et al, 2012; Han et al, 2012; Song et al, 2012; Talchai et al, 2012; Thier et al, 2012; Najm et al, 2013; Yang et al, 2013)
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