Activation of pancreatic-duct-derived progenitor cells during pancreas regeneration in adult rats.
The adult pancreas has considerable capacity to regenerate in response to injury. We hypothesized that after partial pancreatectomy (Px) in adult rats, pancreatic-duct cells serve as a source of regeneration by undergoing a reproducible dedifferentiation and redifferentiation. We support this hypothesis by the detection of an early loss of the ductal differentiation marker Hnf6 in the mature ducts, followed by the transient appearance of areas composed of proliferating ductules, called foci of regeneration, which subsequently form new pancreatic lobes. In young foci, ductules express markers of the embryonic pancreatic epithelium - Pdx1, Tcf2 and Sox9 - suggesting that these cells act as progenitors of the regenerating pancreas. The endocrine-lineage-specific transcription factor Neurogenin3, which is found in the developing embryonic pancreas, was transiently detected in the foci. Islets in foci initially resemble embryonic islets in their lack of MafA expression and lower percentage of beta-cells, but with increasing maturation have increasing numbers of MafA(+) insulin(+) cells. Taken together, we provide a mechanism by which adult pancreatic duct cells recapitulate aspects of embryonic pancreas differentiation in response to injury, and contribute to regeneration of the pancreas. This mechanism of regeneration relies mainly on the plasticity of the differentiated cells within the pancreas.
Li
Wan-Chun
WC
Section of Islet Transplantation and Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
Rukstalis
J Michael
JM
Nishimura
Wataru
W
Tchipashvili
Vaja
V
Habener
Joel F
JF
Sharma
Arun
A
Bonner-Weir
Susan
S
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051559:Hepatocyte Nuclear Factor 6 / Q000172:deficiency / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010179:Pancreas / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D010180:Pancreatectomy; D010183:Pancreatic Ducts / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration / Q000502:physiology*; D014157:Transcription Factors / Q000172:deficiency / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D051559:Hepatocyte Nuclear Factor 6; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; C498696:Neurog3 protein, rat; C496607:Onecut1 protein, rat