α-
cells, which synthesize
glucagon, also support β-
cell survival and have the capacity to transdifferentiate into β-
cells. However, the
role of α-
cells in pathological conditions and their putative clinical applications remain elusive due in large part to the lack of mature α-
cells. Here, we present a new
technique to generate functional α-like
cells. α-like
cells (iAlpha
cells) were generated from
mouse fibroblasts by transduction of
transcription factors, including Hhex, Foxa3, Gata4, Pdx1 and Pax4, which induce α-
cell-specific
gene expression and
glucagon secretion in response to KCl and Arg stimulation. The
cell functions in vivo and
in vitro were evaluated. Lineage-specific and functional-related
gene expression was tested by realtime
PCR,
insulin tolerance test (ITT),
glucose tolerance test (GTT), Ki67 and
glucagon immunohistochemistry analysis were done in iAlpha
cells transplanted
nude mice. iAlpha
cells possess α-
cell function
in vitro and alter
blood glucose levels in vivo.
Transplantation of iAlpha
cells into
nude mice resulted in
insulin resistance and increased β-
cell proliferation. Taken together, we present a novel strategy to generate functional α-like
cells for the purposes of
disease modeling and
regenerative medicine.