Hepatocyte growth factor enhances engraftment and function of nonhuman primate islets

Nathalie M. Fiaschi-Taesch, Dora Berman-Weinberg, Brian M. Sicari, Karen K. Takane, Adolfo Garcia-Ocaña, Camillo Ricordi, Norma S Kenyon, Andrew F. Stewart

Research output: Contribution to journalArticle

Abstract

OBJECTIVE-Adenoviral delivery of hepatocyte growth factor (HGF) to rodent islets improves islet graft survival and function, markedly reducing the number of islets required to achieve glucose control. Here, we asked whether these prior observations in rodent models extend to nonhuman primate (NHP) islets. RESEARCH DESIGN AND METHODS-NHP islets were transduced with murine (Ad.mHGF) or human (Ad.hHGF) adenoviral HGF (Ad.HGF) at low multiplicity of infection and studied in vitro. To study the function of Ad.HGF-transduced NHP islets in vivo, a renal subcapsular marginal mass islet transplant model was developed in streptozotocin-induced diabetic NOD-SCID mice. RESULTS-Baseline glucose values were 454.7 ± 11.3 mg/dl (n = 7). Transplant of 500 NHP islet equivalents (IE) had only a marginal effect on blood glucose (369.1 ± 9.7 mg/dl, n = 5). In striking contrast, 500 NHP IE transduced with Ad.mHGF promptly and continuously corrected blood glucose (142.0 ± 6.2 mg/dl, n = 7) for the 6-week duration of the experiment. Unilateral nephrectomy resulted in an immediate return of glucose to baseline diabetic levels. Interestingly, adenoviral DNA, as well as mouse HGF (mHGF) mRNA derived from the adenovirus, were present for 42 days posttransplantation. Surprisingly, transplant of 500 IE with Ad.hHGF, as compared with Ad.mHGF, resulted in only marginal correction of blood glucose, suggesting that human HGF is less efficient than mHGF in this system. CONCLUSIONS-These studies demonstrate that mHGF markedly improves islet transplant outcomes in the highest preclinical species examined to date. HGF has promise as an agent that can improve islet mass and function in transplant models and likely in other models of types 1 and 2 diabetes.

Original languageEnglish
Pages (from-to)2745-2754
Number of pages10
JournalDiabetes
Volume57
Issue number10
DOIs
StatePublished - Oct 1 2008

Fingerprint

Hepatocyte Growth Factor
Primates
Transplants
Blood Glucose
Glucose
Rodentia
Inbred NOD Mouse
SCID Mice
Graft Survival
Streptozocin
Nephrectomy
Type 1 Diabetes Mellitus
Adenoviridae
Type 2 Diabetes Mellitus
Research Design
Kidney
Messenger RNA
DNA
Infection

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Fiaschi-Taesch, N. M., Berman-Weinberg, D., Sicari, B. M., Takane, K. K., Garcia-Ocaña, A., Ricordi, C., ... Stewart, A. F. (2008). Hepatocyte growth factor enhances engraftment and function of nonhuman primate islets. Diabetes, 57(10), 2745-2754. https://doi.org/10.2337/db08-1085

Hepatocyte growth factor enhances engraftment and function of nonhuman primate islets. / Fiaschi-Taesch, Nathalie M.; Berman-Weinberg, Dora; Sicari, Brian M.; Takane, Karen K.; Garcia-Ocaña, Adolfo; Ricordi, Camillo; Kenyon, Norma S; Stewart, Andrew F.

In: Diabetes, Vol. 57, No. 10, 01.10.2008, p. 2745-2754.

Research output: Contribution to journalArticle

Fiaschi-Taesch, NM, Berman-Weinberg, D, Sicari, BM, Takane, KK, Garcia-Ocaña, A, Ricordi, C, Kenyon, NS & Stewart, AF 2008, 'Hepatocyte growth factor enhances engraftment and function of nonhuman primate islets', Diabetes, vol. 57, no. 10, pp. 2745-2754. https://doi.org/10.2337/db08-1085
Fiaschi-Taesch, Nathalie M. ; Berman-Weinberg, Dora ; Sicari, Brian M. ; Takane, Karen K. ; Garcia-Ocaña, Adolfo ; Ricordi, Camillo ; Kenyon, Norma S ; Stewart, Andrew F. / Hepatocyte growth factor enhances engraftment and function of nonhuman primate islets. In: Diabetes. 2008 ; Vol. 57, No. 10. pp. 2745-2754.
@article{ecc59a60ffa24a76bbb57902aeb1f2e2,
title = "Hepatocyte growth factor enhances engraftment and function of nonhuman primate islets",
abstract = "OBJECTIVE-Adenoviral delivery of hepatocyte growth factor (HGF) to rodent islets improves islet graft survival and function, markedly reducing the number of islets required to achieve glucose control. Here, we asked whether these prior observations in rodent models extend to nonhuman primate (NHP) islets. RESEARCH DESIGN AND METHODS-NHP islets were transduced with murine (Ad.mHGF) or human (Ad.hHGF) adenoviral HGF (Ad.HGF) at low multiplicity of infection and studied in vitro. To study the function of Ad.HGF-transduced NHP islets in vivo, a renal subcapsular marginal mass islet transplant model was developed in streptozotocin-induced diabetic NOD-SCID mice. RESULTS-Baseline glucose values were 454.7 ± 11.3 mg/dl (n = 7). Transplant of 500 NHP islet equivalents (IE) had only a marginal effect on blood glucose (369.1 ± 9.7 mg/dl, n = 5). In striking contrast, 500 NHP IE transduced with Ad.mHGF promptly and continuously corrected blood glucose (142.0 ± 6.2 mg/dl, n = 7) for the 6-week duration of the experiment. Unilateral nephrectomy resulted in an immediate return of glucose to baseline diabetic levels. Interestingly, adenoviral DNA, as well as mouse HGF (mHGF) mRNA derived from the adenovirus, were present for 42 days posttransplantation. Surprisingly, transplant of 500 IE with Ad.hHGF, as compared with Ad.mHGF, resulted in only marginal correction of blood glucose, suggesting that human HGF is less efficient than mHGF in this system. CONCLUSIONS-These studies demonstrate that mHGF markedly improves islet transplant outcomes in the highest preclinical species examined to date. HGF has promise as an agent that can improve islet mass and function in transplant models and likely in other models of types 1 and 2 diabetes.",
author = "Fiaschi-Taesch, {Nathalie M.} and Dora Berman-Weinberg and Sicari, {Brian M.} and Takane, {Karen K.} and Adolfo Garcia-Oca{\~n}a and Camillo Ricordi and Kenyon, {Norma S} and Stewart, {Andrew F.}",
year = "2008",
month = "10",
day = "1",
doi = "10.2337/db08-1085",
language = "English",
volume = "57",
pages = "2745--2754",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "10",

}

TY - JOUR

T1 - Hepatocyte growth factor enhances engraftment and function of nonhuman primate islets

AU - Fiaschi-Taesch, Nathalie M.

AU - Berman-Weinberg, Dora

AU - Sicari, Brian M.

AU - Takane, Karen K.

AU - Garcia-Ocaña, Adolfo

AU - Ricordi, Camillo

AU - Kenyon, Norma S

AU - Stewart, Andrew F.

PY - 2008/10/1

Y1 - 2008/10/1

N2 - OBJECTIVE-Adenoviral delivery of hepatocyte growth factor (HGF) to rodent islets improves islet graft survival and function, markedly reducing the number of islets required to achieve glucose control. Here, we asked whether these prior observations in rodent models extend to nonhuman primate (NHP) islets. RESEARCH DESIGN AND METHODS-NHP islets were transduced with murine (Ad.mHGF) or human (Ad.hHGF) adenoviral HGF (Ad.HGF) at low multiplicity of infection and studied in vitro. To study the function of Ad.HGF-transduced NHP islets in vivo, a renal subcapsular marginal mass islet transplant model was developed in streptozotocin-induced diabetic NOD-SCID mice. RESULTS-Baseline glucose values were 454.7 ± 11.3 mg/dl (n = 7). Transplant of 500 NHP islet equivalents (IE) had only a marginal effect on blood glucose (369.1 ± 9.7 mg/dl, n = 5). In striking contrast, 500 NHP IE transduced with Ad.mHGF promptly and continuously corrected blood glucose (142.0 ± 6.2 mg/dl, n = 7) for the 6-week duration of the experiment. Unilateral nephrectomy resulted in an immediate return of glucose to baseline diabetic levels. Interestingly, adenoviral DNA, as well as mouse HGF (mHGF) mRNA derived from the adenovirus, were present for 42 days posttransplantation. Surprisingly, transplant of 500 IE with Ad.hHGF, as compared with Ad.mHGF, resulted in only marginal correction of blood glucose, suggesting that human HGF is less efficient than mHGF in this system. CONCLUSIONS-These studies demonstrate that mHGF markedly improves islet transplant outcomes in the highest preclinical species examined to date. HGF has promise as an agent that can improve islet mass and function in transplant models and likely in other models of types 1 and 2 diabetes.

AB - OBJECTIVE-Adenoviral delivery of hepatocyte growth factor (HGF) to rodent islets improves islet graft survival and function, markedly reducing the number of islets required to achieve glucose control. Here, we asked whether these prior observations in rodent models extend to nonhuman primate (NHP) islets. RESEARCH DESIGN AND METHODS-NHP islets were transduced with murine (Ad.mHGF) or human (Ad.hHGF) adenoviral HGF (Ad.HGF) at low multiplicity of infection and studied in vitro. To study the function of Ad.HGF-transduced NHP islets in vivo, a renal subcapsular marginal mass islet transplant model was developed in streptozotocin-induced diabetic NOD-SCID mice. RESULTS-Baseline glucose values were 454.7 ± 11.3 mg/dl (n = 7). Transplant of 500 NHP islet equivalents (IE) had only a marginal effect on blood glucose (369.1 ± 9.7 mg/dl, n = 5). In striking contrast, 500 NHP IE transduced with Ad.mHGF promptly and continuously corrected blood glucose (142.0 ± 6.2 mg/dl, n = 7) for the 6-week duration of the experiment. Unilateral nephrectomy resulted in an immediate return of glucose to baseline diabetic levels. Interestingly, adenoviral DNA, as well as mouse HGF (mHGF) mRNA derived from the adenovirus, were present for 42 days posttransplantation. Surprisingly, transplant of 500 IE with Ad.hHGF, as compared with Ad.mHGF, resulted in only marginal correction of blood glucose, suggesting that human HGF is less efficient than mHGF in this system. CONCLUSIONS-These studies demonstrate that mHGF markedly improves islet transplant outcomes in the highest preclinical species examined to date. HGF has promise as an agent that can improve islet mass and function in transplant models and likely in other models of types 1 and 2 diabetes.

UR - http://www.scopus.com/inward/record.url?scp=58149359299&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58149359299&partnerID=8YFLogxK

U2 - 10.2337/db08-1085

DO - 10.2337/db08-1085

M3 - Article

C2 - 18820214

VL - 57

SP - 2745

EP - 2754

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 10

ER -