Streptozotocin-induced partial beta cell depletion in nude mice without hyperglycaemia induces pancreatic morphogenesis in transplanted embryonic stem cells.
OBJECTIVE
It appears that the adult pancreas has limited regenerative ability following beta cell destruction by streptozotocin (STZ). However, it is not clear if this limitation is due to an inability to respond to, rather than an absence of, regenerative stimuli. In this study we aimed to uncouple the regenerative signal from the regenerative response by using an exogenous stem cell source to detect regenerative stimuli produced by the STZ-injured pancreas at physiological blood glucose levels.


METHODS
Adult nude mice received 150 mg/kg STZ and 1x10(6) J1 mouse embryonic stem (ES) cells by i.p. injection. Permanent beta cell depletion of 50% was estimated from the ratio of beta:alpha cells in pancreata from STZ-treated mice compared with control animals after 24 days.


RESULTS
Transplanted ES cells homed to the STZ-injured pancreas and formed tumours. Immunocytochemical analysis of pancreas-associated ES tumours revealed foci containing insulin/PDX-1 double-positive and glucagon-positive/PDX-1-negative cell clusters associated with PDX-1-positive columnar lumenal epithelium and extensive alpha-amylase-positive pancreatic acini comprising approximately 0.1% of ES tumour volume.


CONCLUSIONS
These data indicate that (1) the adult pancreas produces a milieu of regenerative stimuli following beta cell destruction, and (2) this is not dependent on hyperglycaemic conditions; (3) these regenerative stimuli appear to recapitulate the signalling pathways of embryonic development, since both exocrine and endocrine lineages are produced from PDX-1-positive precursor epithelium. This model will be useful for characterising the regenerative mechanisms in the adult pancreas.
Takeshita
F
F
Section for Studies on Metastasis, National Cancer Center Research Institute, 1-1 Tsukiji, 5-chome, Tokyo, Japan.
Kodama
M
M
Yamamoto
H
H
Ikarashi
Y
Y
Ueda
S
S
Teratani
T
T
Yamamoto
Y
Y
Tamatani
T
T
Kanegasaki
S
S
Ochiya
T
T
Quinn
G
G
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000166:cytology / Q000637:transplantation*; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D009024:Morphogenesis; D010179:Pancreas / Q000254:growth & development*; D013311:Streptozocin / Q000494:pharmacology*
D001786:Blood Glucose; D013311:Streptozocin