Rapamycin impairs in vivo proliferation of islet beta-cells

Elsie Zahr, Ruth Molano, Antonello Pileggi, Hirohito Ichii, Sergio San Jose, Nicola Bocca, Weijun An, Jorge Gonzalez-Quintana, Christopher Fraker, Camillo Ricordi, Luca A Inverardi

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

BACKGROUND. Progressive graft dysfunction is commonly observed in recipients of islet allografts treated with high doses of rapamycin. This study aimed at evaluating the effect of rapamycin on pancreatic islet cell proliferation in vivo. METHODS. The murine pregnancy model was utilized, since a high rate of β-cell proliferation occurs in a well-defined time frame. Rapamycin (0.2 mg/kg/day) was given to C57BL/6 mice for 5-7 days starting on day 7.5 of pregnancy. Cell proliferation was evaluated by detection of bromodeoxyuridine incorporation by immunohistochemistry. RESULTS. Pregnancy led to increased β-cell proliferation and islet yield with skewing in islet size distribution as well as higher pancreatic insulin content, when compared to that of nonpregnant females. These effects of pregnancy on β-cell proliferation and mass were significantly blunted by rapamycin treatment. Minimal effect of rapamycin was observed on islet function both in vivo and in vitro. Rapamycin treatment of islets in vitro resulted in reduced p70s6k phosphorylation, which was paralleled by increased ERK1/2 phosphorylation. CONCLUSIONS. Rapamycin treatment reduces the rate of β-cell proliferation in vivo. This phenomenon may contribute to impair β-cell renewal in transplanted patients and to the progressive dysfunction observed in islet graft recipients.

Original languageEnglish
Pages (from-to)1576-1583
Number of pages8
JournalTransplantation
Volume84
Issue number12
DOIs
StatePublished - Dec 1 2007

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Sirolimus
Islets of Langerhans
Cell Proliferation
Pregnancy
Phosphorylation
70-kDa Ribosomal Protein S6 Kinases
Transplants
Bromodeoxyuridine
Inbred C57BL Mouse
Allografts
Therapeutics
Immunohistochemistry
Insulin

Keywords

  • Beta-cells
  • Islet transplantation
  • Islets of Langerhans
  • Mice
  • mTOR
  • Pregnancy
  • Proliferation
  • Rapamycin

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Zahr, E., Molano, R., Pileggi, A., Ichii, H., Jose, S. S., Bocca, N., ... Inverardi, L. A. (2007). Rapamycin impairs in vivo proliferation of islet beta-cells. Transplantation, 84(12), 1576-1583. https://doi.org/10.1097/01.tp.0000296035.48728.28

Rapamycin impairs in vivo proliferation of islet beta-cells. / Zahr, Elsie; Molano, Ruth; Pileggi, Antonello; Ichii, Hirohito; Jose, Sergio San; Bocca, Nicola; An, Weijun; Gonzalez-Quintana, Jorge; Fraker, Christopher; Ricordi, Camillo; Inverardi, Luca A.

In: Transplantation, Vol. 84, No. 12, 01.12.2007, p. 1576-1583.

Research output: Contribution to journalArticle

Zahr, E, Molano, R, Pileggi, A, Ichii, H, Jose, SS, Bocca, N, An, W, Gonzalez-Quintana, J, Fraker, C, Ricordi, C & Inverardi, LA 2007, 'Rapamycin impairs in vivo proliferation of islet beta-cells', Transplantation, vol. 84, no. 12, pp. 1576-1583. https://doi.org/10.1097/01.tp.0000296035.48728.28
Zahr E, Molano R, Pileggi A, Ichii H, Jose SS, Bocca N et al. Rapamycin impairs in vivo proliferation of islet beta-cells. Transplantation. 2007 Dec 1;84(12):1576-1583. https://doi.org/10.1097/01.tp.0000296035.48728.28
Zahr, Elsie ; Molano, Ruth ; Pileggi, Antonello ; Ichii, Hirohito ; Jose, Sergio San ; Bocca, Nicola ; An, Weijun ; Gonzalez-Quintana, Jorge ; Fraker, Christopher ; Ricordi, Camillo ; Inverardi, Luca A. / Rapamycin impairs in vivo proliferation of islet beta-cells. In: Transplantation. 2007 ; Vol. 84, No. 12. pp. 1576-1583.
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abstract = "BACKGROUND. Progressive graft dysfunction is commonly observed in recipients of islet allografts treated with high doses of rapamycin. This study aimed at evaluating the effect of rapamycin on pancreatic islet cell proliferation in vivo. METHODS. The murine pregnancy model was utilized, since a high rate of β-cell proliferation occurs in a well-defined time frame. Rapamycin (0.2 mg/kg/day) was given to C57BL/6 mice for 5-7 days starting on day 7.5 of pregnancy. Cell proliferation was evaluated by detection of bromodeoxyuridine incorporation by immunohistochemistry. RESULTS. Pregnancy led to increased β-cell proliferation and islet yield with skewing in islet size distribution as well as higher pancreatic insulin content, when compared to that of nonpregnant females. These effects of pregnancy on β-cell proliferation and mass were significantly blunted by rapamycin treatment. Minimal effect of rapamycin was observed on islet function both in vivo and in vitro. Rapamycin treatment of islets in vitro resulted in reduced p70s6k phosphorylation, which was paralleled by increased ERK1/2 phosphorylation. CONCLUSIONS. Rapamycin treatment reduces the rate of β-cell proliferation in vivo. This phenomenon may contribute to impair β-cell renewal in transplanted patients and to the progressive dysfunction observed in islet graft recipients.",
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AU - Pileggi, Antonello

AU - Ichii, Hirohito

AU - Jose, Sergio San

AU - Bocca, Nicola

AU - An, Weijun

AU - Gonzalez-Quintana, Jorge

AU - Fraker, Christopher

AU - Ricordi, Camillo

AU - Inverardi, Luca A

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N2 - BACKGROUND. Progressive graft dysfunction is commonly observed in recipients of islet allografts treated with high doses of rapamycin. This study aimed at evaluating the effect of rapamycin on pancreatic islet cell proliferation in vivo. METHODS. The murine pregnancy model was utilized, since a high rate of β-cell proliferation occurs in a well-defined time frame. Rapamycin (0.2 mg/kg/day) was given to C57BL/6 mice for 5-7 days starting on day 7.5 of pregnancy. Cell proliferation was evaluated by detection of bromodeoxyuridine incorporation by immunohistochemistry. RESULTS. Pregnancy led to increased β-cell proliferation and islet yield with skewing in islet size distribution as well as higher pancreatic insulin content, when compared to that of nonpregnant females. These effects of pregnancy on β-cell proliferation and mass were significantly blunted by rapamycin treatment. Minimal effect of rapamycin was observed on islet function both in vivo and in vitro. Rapamycin treatment of islets in vitro resulted in reduced p70s6k phosphorylation, which was paralleled by increased ERK1/2 phosphorylation. CONCLUSIONS. Rapamycin treatment reduces the rate of β-cell proliferation in vivo. This phenomenon may contribute to impair β-cell renewal in transplanted patients and to the progressive dysfunction observed in islet graft recipients.

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