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Hepatocyte growth factor enhances engraftment and function of nonhuman primate islets.

Fiaschi-Taesch NM, Berman DM, Sicari BM, Takane KK, Garcia-Ocaña A, Ricordi C, Kenyon NS, Stewart AF - Diabetes (2008)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. taeschn@dom.pitt.edu

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.

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Blood glucose levels in STZ-induced diabetic NOD-SCID mice transplanted with uninfected or infected NHP islets. A: Defining the NHP marginal mass. At 24 h after mock transduction, 500, 1,000, or 2,000 IE of NHP islets were transplanted under the kidney capsule of STZ-induced NOD-SCID mice. Identical surgery was performed on the sham-operated animals, except that they received saline instead of islets. Results are the means ± SE of four to seven animals per condition. At day 42, unilateral nephrectomy (UNX) was performed in mice transplanted with either 1,000 or 2,000 control IE or with 500 Ad.mHGF IE, and the blood glucose returned immediately to pretransplant diabetic levels. B: Effect of Ad.HGF on NHP islet transplant outcome. At 24 h after transduction, 500 Ad.LacZ, Ad.mHGF, or Ad.hHGF IE were transplanted under the kidney capsule of STZ-induced NOD-SCID mice. Results are the means ± SE of five to seven animals per condition.
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f3: Blood glucose levels in STZ-induced diabetic NOD-SCID mice transplanted with uninfected or infected NHP islets. A: Defining the NHP marginal mass. At 24 h after mock transduction, 500, 1,000, or 2,000 IE of NHP islets were transplanted under the kidney capsule of STZ-induced NOD-SCID mice. Identical surgery was performed on the sham-operated animals, except that they received saline instead of islets. Results are the means ± SE of four to seven animals per condition. At day 42, unilateral nephrectomy (UNX) was performed in mice transplanted with either 1,000 or 2,000 control IE or with 500 Ad.mHGF IE, and the blood glucose returned immediately to pretransplant diabetic levels. B: Effect of Ad.HGF on NHP islet transplant outcome. At 24 h after transduction, 500 Ad.LacZ, Ad.mHGF, or Ad.hHGF IE were transplanted under the kidney capsule of STZ-induced NOD-SCID mice. Results are the means ± SE of five to seven animals per condition.

Mentions: Our previous studies had shown that mHGF overexpression improves islet transplant outcomes in two mouse models and a rat model of islet transplantation (4–6). The principal goal of the current study was to determine whether this applies to islets of higher species. We first needed to define a fully therapeutic as well as a marginal mass of NHP islets in NOD-SCID mice. Sham-transplanted mice remained severely hyperglycemic throughout the study (Fig. 3A). In contrast, mice transplanted with 500 IE achieved borderline improvement in blood glucose, and 1,000 IE or 2,000 IE was sufficient to achieve stable euglycemia. Therefore, we selected 500 IE as the marginal mass. To determine whether adenoviral infection influenced NHP islet function or engraftment, we also studied 500 NHP IE transduced with Ad.LacZ. As shown in Fig. 3B, these behaved comparably with 500 nontransduced normal NHP islets. In marked contrast to these controls, 500 IE infected with Ad.mHGF were able to reduce blood glucose concentrations to the near-normal postprandial range (Fig. 3B). These findings clearly demonstrate that Ad.mHGF enhances NHP islet engraftment and function.


Hepatocyte growth factor enhances engraftment and function of nonhuman primate islets.

Fiaschi-Taesch NM, Berman DM, Sicari BM, Takane KK, Garcia-Ocaña A, Ricordi C, Kenyon NS, Stewart AF - Diabetes (2008)

Blood glucose levels in STZ-induced diabetic NOD-SCID mice transplanted with uninfected or infected NHP islets. A: Defining the NHP marginal mass. At 24 h after mock transduction, 500, 1,000, or 2,000 IE of NHP islets were transplanted under the kidney capsule of STZ-induced NOD-SCID mice. Identical surgery was performed on the sham-operated animals, except that they received saline instead of islets. Results are the means ± SE of four to seven animals per condition. At day 42, unilateral nephrectomy (UNX) was performed in mice transplanted with either 1,000 or 2,000 control IE or with 500 Ad.mHGF IE, and the blood glucose returned immediately to pretransplant diabetic levels. B: Effect of Ad.HGF on NHP islet transplant outcome. At 24 h after transduction, 500 Ad.LacZ, Ad.mHGF, or Ad.hHGF IE were transplanted under the kidney capsule of STZ-induced NOD-SCID mice. Results are the means ± SE of five to seven animals per condition.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2551685&req=5

f3: Blood glucose levels in STZ-induced diabetic NOD-SCID mice transplanted with uninfected or infected NHP islets. A: Defining the NHP marginal mass. At 24 h after mock transduction, 500, 1,000, or 2,000 IE of NHP islets were transplanted under the kidney capsule of STZ-induced NOD-SCID mice. Identical surgery was performed on the sham-operated animals, except that they received saline instead of islets. Results are the means ± SE of four to seven animals per condition. At day 42, unilateral nephrectomy (UNX) was performed in mice transplanted with either 1,000 or 2,000 control IE or with 500 Ad.mHGF IE, and the blood glucose returned immediately to pretransplant diabetic levels. B: Effect of Ad.HGF on NHP islet transplant outcome. At 24 h after transduction, 500 Ad.LacZ, Ad.mHGF, or Ad.hHGF IE were transplanted under the kidney capsule of STZ-induced NOD-SCID mice. Results are the means ± SE of five to seven animals per condition.
Mentions: Our previous studies had shown that mHGF overexpression improves islet transplant outcomes in two mouse models and a rat model of islet transplantation (4–6). The principal goal of the current study was to determine whether this applies to islets of higher species. We first needed to define a fully therapeutic as well as a marginal mass of NHP islets in NOD-SCID mice. Sham-transplanted mice remained severely hyperglycemic throughout the study (Fig. 3A). In contrast, mice transplanted with 500 IE achieved borderline improvement in blood glucose, and 1,000 IE or 2,000 IE was sufficient to achieve stable euglycemia. Therefore, we selected 500 IE as the marginal mass. To determine whether adenoviral infection influenced NHP islet function or engraftment, we also studied 500 NHP IE transduced with Ad.LacZ. As shown in Fig. 3B, these behaved comparably with 500 nontransduced normal NHP islets. In marked contrast to these controls, 500 IE infected with Ad.mHGF were able to reduce blood glucose concentrations to the near-normal postprandial range (Fig. 3B). These findings clearly demonstrate that Ad.mHGF enhances NHP islet engraftment and function.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. taeschn@dom.pitt.edu

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.

Show MeSH
Related in: MedlinePlus