Skip to main content
NCBI home page
Islets logoLink to Islets
. 2012 Mar 1;4(2):138–144. doi: 10.4161/isl.19491

Partial hepatectomy improves the outcome of intraportal islet transplantation by promoting revascularization

Yukihiko Saito 1,2, Nathaniel K Chan 1, Eba Hathout 1,*
PMCID: PMC3396702  PMID: 22622159

Abstract

Revascularization of grafts is one of the important key factors for the success of islet transplantation. After partial hepatectomy, many growth factors such as hepatocyte growth factor and vascular endothelial growth factor are increased in the remnant liver. These growth factors have properties that promote angiogenesis. This might be an optimal environment for revascularization of islets transplanted intraportally. To verify this hypothesis, syngeneic islets (330 per recipient) were transplanted into the right hepatic lobes of streptozotocin-induced diabetic Balb/c mice with (hepatectomy group) or without (control group) left liver resection. Blood glucose was monitored for 28 d after transplantation. Glucose tolerance test was performed on post-operative day (POD) 30, and histological assessments were performed on POD 7 and 30 respectively. Analysis revealed that 36.7% of the control and 90.0% of the hepatectomy mice attained normoglycemia during the observation period (*p = 0.0142). Glucose tolerance was improved in the hepatectomy group (Area under the curve of intraperitoneal glucose tolerance tests on POD 30, Control; 47,700 ± 5,890 min*mg/dl, Hepatectomy; 26,000 ± 2,060 min*mg/dl: **p = 0.00314). Revascularization of grafted islets was more pronounced in the hepatectomy group (Vessel number per islet area on POD 7, Control; 3.20 ± 0.463 × 10−4/µm2, Hepatectomy; 7.08 ± 0.513 × 10−4/µm2: **p < 0.01). In the present study, partial hepatectomy (30%) improved the outcome of intraportal islet transplantation. Revascularization of islets transplanted into the liver may have been promoted by the induction of liver regeneration.

Keywords: diabetes, intraportal, islet transplantation, partial hepatectomy, revascularization

Introduction

Islet transplantation has become a viable therapy for type 1 diabetes mellitus. Although the Edmonton protocol introduced various suggestions for the improvement of islet transplantation,1 there is a concern of deteriorating graft function over time.2 In addition, while single-donor islet transplantation success has been achieved,3-5 most centers still rely on multiple donor organs to achieve initial insulin independence.6

One approach to improving the function of transplanted islets may be manipulation of the transplant site. Currently, the liver is considered the most suitable site for clinical islet transplantation. The liver has a well-known regenerative capability after either partial removal of its parenchymal mass or various hepatocyte insults.7,8 This may offer a particularly rich environment for islets transplanted intraportally. Sudo et al. showed that graft function was improved after intraportal islet transplantation with 70% partial hepatectomy in a rodent model.9 However, the reason of this excellent result is still unknown.

Although native islets in the pancreas have a rich microvasculature, islet blood vessels are disrupted during islet isolation. Proper revascularization of the transplanted islets is of great importance for the function and survival of islet grafts. After partial hepatectomy, many growth factors such as hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) are upregulated for regeneration in the remnant liver.7,8 It is known that these growth factors have properties to promote vascularization.10,11 Therefore, we hypothesized that revascularization of transplanted islets was enhanced during liver regeneration after partial hepatectomy.

In this study, we performed intraportal islet transplantation with (hepatectomy group) or without (control group) 30% partial hepatectomy in a mouse model. Improvement of graft function and promotion of revascularization of transplanted islets were observed in the hepatectomy group. The induction of liver regeneration might be one of the promising strategies to improve the outcome of intraportal islet transplantation.

Results

Functional tests of transplanted islets

Blood glucose data of each animal in the control group is shown in Figure 1A, and that in the hepatectomy group is shown in Figure 1B. During the observation period, 36.7% of the control and 90.0% of the hepatectomy mice attained normoglycemia (*p = 0.0142) (Fig. 1C). Area under the curve of intraperitoneal glucose tolerance tests (IPGTT) on postoperative days (POD) 30 in the control group was significantly higher than that of the hepatectomy group (Control; 47,700 ± 5,890 min*mg/dl, Hepatectomy; 26,000 ± 2,060 min*mg/dl: **p = 0.00609) (Fig. 1D).

graphic file with name isl-4-138-g1.jpg

Open in a new tab

Figure 1. Effect of partial hepatectomy after intraportal islet transplantation on glucose control (A and B). Streptozotocin-induced diabetic Balb/c mice received 330 syngeneic islets, with a diameter of around 150µm, into right hepatic lobes with or without left liver resection. Achievement of normoglycemia was defined as a non-fasting blood glucose level of ≤ 11 mmol/L (200 mg/dL) on two consecutive measurements. Black triangles represent recipient blood glucose level measured for 28 d (n = 6), and white triangles represent recipient blood glucose level measured for 7 d (n = 4) in the control group (A). Black squares represent recipient blood glucose level measured for 28 d (n = 6), and white squares represent recipient blood glucose level measured for 7 d (n = 4) in the hepatectomy group (B). Bold lines represent parameters of normal glycemic mice in both groups. Analysis of euglycemic conversion (C). During the observation period, 36.7% of the control and 90.0% of the hepatectomy mice attained normoglycemia (*p = 0.0142). Intraperitoneal glucose tolerance tests (IPGTT) on POD 30 (D). IPGTT was performed by overnight fasting for 12 h and then injecting mice with 2.0 g/kg body weight of glucose solution followed by tail vein blood samples at 0, 15, 30, 60, 90 and 120 min after injection. Area under the curve of IPGTT in the control group was significantly higher than that of the NGF-treated group (Control; 47,700 ± 5,890 min*mg/dl, Hepatectomy; 26,000 ± 2,060 min*mg/dl: **p = 0.00609). Data are reported as the mean ± standard error of the mean.

Body weight of the recipients and ratio of the weight of right liver lobes relative to total body weight

There was no significant difference in the time course effect of recipient body weight between these groups (p = 0.659). Animals gained weight after transplantation in both groups (Fig. 2A). Average ratio of the weight of right liver lobes relative to total body weight in the hepatectomy group was 28.4% higher than that in the control group (Control; 0.0162 ± 0.000692, Hepatectomy; 0.0208 ± 0.000968: **p = 0.00314) (Fig. 2B).

graphic file with name isl-4-138-g2.jpg

Open in a new tab

Figure 2. Time course effect of recipient body weight (A). To check food intake in the perioperative period, the body weight of the 6 recipients in both groups was monitored at the time of STZ injection, surgery, and on POD 7, 14, 21 and 28, and that of the 4 recipients in both groups was monitored at the time of STZ injection, surgery, and on POD 7. There was no significant differences in the time course effect of recipient body weight between these groups (p = 0.659). Animals gained weight after transplantation in both groups. Ratio of the weight of right liver lobes relative to total body weight (B). Control and Hepatectomy mice were euthanized on POD 30, and growth of the right liver lobes (transplant site) after partial hepatectomy was evaluated. Average ratio of the weight of right liver lobes relative to total body weight in the hepatectomy group was 28.5% higher than that in the control group (Control; 0.0162 ± 0.000692, Hepatectomy; 0.0208 ± 0.000968: *p = 0.00314). Data are reported as the mean ± standard error of the mean.

Morphology of grafted islets

The number of grafted islets analyzed from 4 mice in the control group was 28 vs. 42 in the hepatectomy group on POD 7, and that analyzed from 6 mice in the control group was 35 vs. 50 in the hepatectomy group on POD 30. Histological analysis of CD31 revealed significantly more blood vessels in contact with or within grafted islets in the hepatectomy group relative to the control group on POD 7 (Control; 3.20 ± 0.463 × 10−4/µm2, Hepatectomy; 7.08 ± 0.513 × 10−4/µm2: **p < 0.01). On POD 30, the number of graft vessels in the hepatectomy group was greater than that in the control groups. However, there were no significant differences between these groups at this time point (Control; 5.65 ± 0.529 × 10−4/µm2, Hepatectomy; 7.10 ± 0.487 × 10−4/µm2) (Fig. 3). The size of grafted islets was equal between the control and hepatectomy groups on POD 7 (Control; 12,600 ± 1,560 µm2, Hepatectomy; 13,900 ± 1,410 µm2). However, grafted islet size in the control group became significantly smaller than that in the hepatectomy group on POD 30 (Control; 8,380 ± 704 µm2, Hepatectomy; 14,400 ± 859 µm2: **p < 0.01) (ANOVA; **p = 0.00101) (Fig. 4A, D, E, H and I). Regarding VEGF expression in grafted islets, there were no positive regions in both groups on POD 7 (Fig. 4C and G). According to the analysis of TdT-mediated dUTP-biotin nick-end labeling (TUNEL) method, there were no apoptotic regions in grafted islets in both groups on POD 7 (Fig. 4B and F).

graphic file with name isl-4-138-g3.jpg

Open in a new tab

Figure 3. Blood vessel numbers of grafted islets on POD 7 and POD 30. Histological staining for CD31 was performed to count the vessel numbers of grafted islets. The number of grafted islets analyzed from 4 mice in the control group was 28 vs. 42 in the hepatectomy group on POD 7, and that analyzed from 6 mice in the control group was 35 vs. 50 in the hepatectomy group on POD 30. More islet blood vessels (positive for CD31) were observed in the hepatectomy group relative to the control group on POD 7 (Control; 3.20 ± 0.463 × 10−4/µm2, Hepatectomy; 7.08 ± 0.513 × 10−4/µm2: **p < 0.01) (A, B and E). On POD 30, the number of graft vessels in the hepatectomy group was greater than in the control groups. However, there were no significant differences between these groups (Control; 5.65 ± 0.529 × 10−4/µm2, Hepatectomy; 7.10 ± 0.487 × 10−4/µm2) (C, D and E). Arrows indicate typical blood vessel morphology in High magnification. The dotted line is drawn along the margin of the transplanted islets. Calibration bar = 100 μm (low magnification) and 20 μm (high magnification). Data are reported as the mean ± standard error of the mean.

graphic file with name isl-4-138-g4.jpg

Open in a new tab

Figure 4. Size of grafted islets on POD 7 and 30, and Apoptotic regions in grafted islets on POD 7. The number of grafted islets analyzed from 4 mice in the control group was 28 vs. 42 in the hepatectomy group on POD 7, and that analyzed from 6 mice in the control group was 35 vs. 50 in the hepatectomy group on POD 30. Insulin staining on POD 7 (A), TUNEL method on POD 7 (B), VEGF staining on POD 7 (C) and Insulin staining on POD 30 (D) were performed in the control group. Insulin staining on POD 7 (E), TUNEL method on POD 7 (F), VEGF staining on POD 7 (G), and Insulin staining on POD 30 (H) were performed in the hepatectomy group. The same islet was used for (A, B and C) and (E, F and G). On POD 7, the size of grafted islets were equal between the control and hepatectomy groups (Control; 12,600 ± 1,560 µm2, Hepatectomy; 13,900 ± 1,410 µm2). However, islet graft size in the hepatectomy group became significantly greater than that in the control group on POD 30 (Control; 8,380 ± 704 µm2, Hepatectomy; 14,400 ± 859 µm2: **p < 0.01). In the control group, the average graft size on POD 30 was almost 50% smaller than that on POD 7. On the other hand, the average graft size in the hepatectomy group did not decrease during the observation period (I). There were no VEGF-positive regions in grafted islets in both groups on POD 7 (C and G). According to the analysis of TUNEL method, there were no apoptotic regions in grafted islets in both groups on POD 7 (B and F). The dotted line is drawn along the margin of the transplanted islets. Calibration bar = 100 μm. Data are reported as the mean ± standard error of the mean.

Discussion

The present study suggests that a nearly 30% partial hepatectomy improves the function of islets transplanted intraportally. Ratio of the weight of right liver lobes (transplant site) relative to total body weight in the hepatectomy group was 28.4% higher than that in the control group. Liver regeneration may be induced after partial hepatectomy combined with intraportal islet transplantation. In terms of time course effect of recipient body weight, there were no differences between the control and hepatectomy group. This result implies that better blood glucose control in the hepatectomy group is not due to less food intake but due to better graft function after transplantation.

To our knowledge, this is the first report that shows that the revascularization of grafted islets in the liver is promoted by partial hepatectomy. Several signals are initiated simultaneously during liver regeneration after partial hepatectomy or liver injury.7,8 HGF and VEGF are abundantly observed in the remnant liver. It was previously reported that HGF improved the early-stage outcome after islet transplantation.12,13 VEGF transferred into islets enhanced islet vascular engraftment and improved islet function in a subcapsular transplant model.14 Golocheikine et al. showed that cooperative signaling between HGF and VEGF enhanced the revascularization of islets transplanted subcutaneously in matrigel.15,16 Looking around these evidences, several growth factors such as HGF and VEGF upregulated by partial hepatectomy might contribute to promote angiogenesis of islets transplanted into liver. However, VEGF expression in grafted islets was unexpectedly not upregulated in both groups on POD 7. One of the reasons for this result might be that the level of VEGF expression in the remnant liver is significantly increased 3 d after partial hepatectomy, and then decreases to near-normal level on POD 7.17 Although we could not reveal the mechanisms for the enhanced vascularization in the hepatectomy group, we speculate that several signals such as HGF and VEGF initiated after partial hepatectomy can promote graft revascularization immediately after intraportal islet transplantation. A causative association remains to be proven.

It has been shown that β-cell proliferation is enhanced by liver regeneration. Morsiani et al. revealed that islets transplanted into the posterior liver lobes of streptozotocin (STZ)-diabetic rats were restored by anterior portal branch ligation, because of the enhancement of β-cell proliferation.18 Dunger et al. demonstrated that DNA replication in mouse pancreatic islets transplanted into the liver was promoted after 40% hepatectomy.19 In addition, HGF was reported to have the potential to promote cell proliferation in islet grafts.12 We observed that the average graft size in the control group on POD 30 was almost 50% smaller relative to that in the same group on POD 7, and significantly smaller than that in the hepatectomy group on POD 30. On the other hand, the average graft size was almost equal during the observation period in the hepatectomy group. This suggests that cell proliferation in the transplanted islets may be poor in the control group compared with the hepatectomy group. Furthermore, there were no apoptotic (TUNEL-positive) regions in grafted islets in either group on POD 7. This result suggests that the apoptotic pathway may not be responsible for the reduced size of transplanted islets. Less revascularization of the grafts and high blood glucose levels might gradually exhaust the transplanted islets several weeks after transplantation.

Although the size of grafted islets was equal on POD 7 between the control and hepatectomy group in this study, there was a significant difference in terms of graft function at this time point. This discrepancy may be due to the early establishment of graft vascularity which helped to ameliorate islet hypoxia in the hepatectomy group. Regenerating liver might actually make a conducive environment for the transplanted islets to be functional.

One of the attractive aspects of current clinical islet transplantation is its less invasive procedural approach.20,21 Looking forward to the clinical applicability of this hepatocyte proliferative strategy, it is important to consider appropriate procedures to promote the liver regeneration. Currently, there are some minimally invasive therapies in the field of liver treatment or surgery, such as transcatheter arterial embolization (TAE), percutaneous ethanol injection therapy (PEIT), percutaneous microwave coagulation therapy (PMCT), radiofrequency ablation (RFA), and the laparoscopic approach for liver resection.22 Selective percutaneous transhepatic portal vein thrombosis may also be effective for the induction of liver regeneration. However, it may carry the risk of portal vein thrombosis or portal venous hypertention23 especially when it is performed with intraportal islet transplantation.20,24 In light of the benefits, we believe that the above approaches are suitable candidates to induce hepatocyte proliferation after islet transplantation. If we transplanted isolated islets into the right liver lobe selectively, we could damage the left liver lobe with these less invasive methods.

Another aspect of the clinical applicability of this study is the difference in regenerative capacity between human and murine islets.25 Before considering clinical application, pre-clinical large animal studies should be performed. Although it may prove difficult to translate this strategy into clinical targets, similar studies can unravel some important clues to improve the outcome of islet transplantation.

In conclusion, we demonstrated that partial hepatectomy of about 30% improved the outcome of intraportal islet transplantation. Revascularization of islets transplanted intraportally was improved by the induction of liver regeneration. Enhanced angiogenesis of transplanted islets might ameliorate their function and contribute to retain their morphology. Further studies are needed to fully elucidate the mechanisms underlying these results.

Materials and Methods

Animals

BALB/c male mice (23–26 g, Charles River) were used as both donors and recipients. The mice were housed under pathogen-free conditions with a 12 h light cycle and free access to food and water. All animal care and treatment procedures were handled in accordance with Principles of Laboratory Animal Care published by the National Institutes of Health (NIH) and approved by the Institutional Animal Care Use Committee.

Induction of diabetes in recipient mice

STZ (200 mg/kg per mouse, Sigma-Aldrich, S0130–1G) was injected intraperitoneally 7 d before transplantation and blood glucose levels were measured by Accu-Chek Aviva glucose monitors (Roche, 03532275004). Mice were transplanted once blood glucose levels were greater than 22 mmol/L (400 mg/dL).

Islet isolation and culture

Murine islets were isolated by collagenase (collagenase V, Sigma-Aldrich, C9263–1G) digestion, separated by Ficoll (Sigma-Aldrich, F4375–500G) discontinuous gradients and purified as previously described.26 Islets were cultured in M199 medium containing 10% fetal bovine serum at 37°C in 5% CO2 and humidified air for 24 h before transplantation.

Intraportal islet transplantation and partial hepatectomy

Recipient mice were anesthetized, and then 330 cultured syngeneic islets, with a diameter of around 150 µm, were transplanted into the right hepatic lobes.27 In the transplantation with hepatectomy group (Hepatectomy; n = 10), almost 30% partial hepatectomy was performed, removing the left liver lobe immediately after islet infusion. Only islet transplantation was performed in the control group (Control; n = 10).

Islet graft functional parameters, harvesting the liver for histological assessment, body weight of the recipients, and ratio of the weight of right liver lobes relative to total body weight

Blood glucose was measured on POD 0, 1, 3, 5, 7, 10, 14, 21 and 28, and IPGTT was performed on POD 30 for 6 mice in both groups. The body weight of them was monitored to check food intake in the perioperative period at the time of STZ injection, surgery, and on POD 7, 14, 21 and 28. IPGTT was performed by overnight fasting for 12 h and then injecting mice with 2.0 g/kg body weight of glucose solution followed by tail vein blood sampling at 0, 15, 30, 60, 90 and 120 min after injection. Blood glucose levels were measured by Accu-Chek Aviva glucose monitors. These mice were sacrificed after IPGTT and the liver was harvested for histological assessments. To evaluate the extent of liver regeneration after partial hepatectomy, the ratio of the weight of right liver lobes (transplant site) relative to body weight was compared before processing for histological analysis (Control; n = 6, Hepatectomy; n = 6). Blood glucose was measured on POD 0, 1, 3, 5, and 7 for 4 mice in both groups. The body weight of them was monitored at the time of STZ injection, surgery, and on POD 7. These mice were sacrificed on POD 7 and the liver was harvested for histological assessments (Control; n = 4, Hepatectomy; n = 4). Achievement of normoglycemia was defined as a non-fasting blood glucose level of ≤ 11 mmol/L (200 mg/dL) on two consecutive measurements.

Histological assessments of insulin, CD31, VEGF, and TUNEL on POD 7

Histological assessments were performed in the harvested livers on POD 7 (Control; n = 4, Hepatectomy; n = 4). The fixed livers were embedded in paraffin and cut in 5-μm thick sections. Staining was performed on four sections from each animal. Specimens were stained by immunohistochemistry for insulin to identify islets. The primary antibody was guinea pig anti-insulin antibody (Dako, IR002) diluted 1:100. After incubating with biotinylated secondary Immunoglobulin G antibody (Vector Laboratories, PK-6101), a peroxidase substrate solution containing AEC+ (Red for insulin, Dako, K3469) was used for visualization and counterstained with hematoxylin. Islets were identified as insulin-positive areas by brightfield microscopy. We assessed the size of functional grafted islets in the all sections. Images were caputured and islet area was manually outlined (ImageJ, NIH) to measure the size. Histological staining for CD31 was performed to count the vessel numbers of each grafted islet. The primary antibody was rabbit anti-CD31 antibody (Abcam, ab28364) diluted 1:50. After incubating with biotinylated secondary Immunoglobulin G antibody (Vector Laboratories, PK-6101), a peroxidase substrate solution containing 3,3′-diaminobenzidine (DAB, Brown for CD31, Dako, K3468) was used for visualization and counterstained with hematoxylin. The blood vessels of grafted islets were identified as CD31 positive zones that were in contact with or within the islets and counted by double-blinded operators at higher magnification (200 × ). We assessed the number of vessels found per area of each grafted islet. Images were captured and islet area was manually outlined (ImageJ) to measure the size. Histological staining for VEGF was performed for ability of vascularization. The primary antibody was goat anti-VEGF antibody (Santa Cruz Biotechnology Inc., sc-1836) diluted 1:50. After incubating with biotinylated secondary Immunoglobulin G antibody (Vector Laboratories, PK-6105), a peroxidase substrate solution containing DAB (Brown for VEGF) was used for visualization and counterstained with hematoxylin. Apoptosis was detected by the TUNEL method using an in situ apoptosis detection kit (Promega, G7130). Sections were treated with proteinase K (Dako, S3020) and incubated with TdT enzyme for 60 min at 37◦C. After washing in phosphate buffered saline, the sections were further incubated with streptavidin horseradish peroxidase solution and visualized with DAB.28

Histological assessment of insulin and CD31 on POD 30

Histological assessment of insulin was performed in the harvested livers on POD 30 (control; n = 6, NGF-treated; n = 6). The fixed livers were embedded in paraffin and cut in 5-μm thick sections. Staining was performed on four sections from each animal. Insulin staining was performed using the same procedure as above. Images were caputured and islet area was manually outlined (ImageJ) to measure the size. CD31 staining was performed and the number of vessels found per area of each grafted islet was assessed, using the same procedure as above.

Statistical analyses

All data are expressed as the mean ± standard error of the mean. Analysis of euglycemic conversion was performed by Kaplan-Meier method with a log-rank test. Comparisons between the two groups were performed by using Student’s t-test. One-factor ANOVA with Bonferroni-Dunn post hoc test was used to determine the time course effect of the analysis for the number of vessels found per area of each grafted islet and size of grafted islets. Repeated measure ANOVA was used to determine the time course effect of the recipient body weight. Statistical significance was established at p < 0.05.

Acknowledgments

This work was supported by NIH/NIDDK grant number DK077541 (EH). We are grateful for the microsurgical technical support by John Chrisler and the kind help in specimen processing by John Hough.

Glossary

Abbreviations:

HGF

hepatocyte growth factor

VEGF

vascular endothelial growth factor

IPGTT

intraperitoneal glucose tolerance tests

POD

postoperative days

TUNEL

TdT-mediated dUTP-biotin nick-end labeling

STZ

Streptozotocin

TAE

transcatheter arterial embolization

PEIT

percutaneous ethanol injection therapy

PMCT

percutaneous microwave coagulation therapy

RFA

radiofrequency ablation

NIH

National Institutes of Health

DAB

3,3′-diaminobenzidine

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed

Footnotes

References

  • 1.Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med. 2000;343:230–8. doi: 10.1056/NEJM200007273430401. [DOI] [PubMed] [Google Scholar]
  • 2.Ryan EA, Paty BW, Senior PA, Bigam D, Alfadhli E, Kneteman NM, et al. Five-year follow-up after clinical islet transplantation. Diabetes. 2005;54:2060–9. doi: 10.2337/diabetes.54.7.2060. [DOI] [PubMed] [Google Scholar]
  • 3.Koh A, Senior P, Salam A, Kin T, Imes S, Dinyari P, et al. Insulin-heparin infusions peritransplant substantially improve single-donor clinical islet transplant success. Transplantation. 2010;89:465–71. doi: 10.1097/TP.0b013e3181c478fd. [DOI] [PubMed] [Google Scholar]
  • 4.Froud T, Ricordi C, Baidal DA, Hafiz MM, Ponte G, Cure P, et al. Islet transplantation in type 1 diabetes mellitus using cultured islets and steroid-free immunosuppression: Miami experience. Am J Transplant. 2005;5:2037–46. doi: 10.1111/j.1600-6143.2005.00957.x. [DOI] [PubMed] [Google Scholar]
  • 5.Hering BJ, Kandaswamy R, Ansite JD, Eckman PM, Nakano M, Sawada T, et al. Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes. JAMA. 2005;293:830–5. doi: 10.1001/jama.293.7.830. [DOI] [PubMed] [Google Scholar]
  • 6.Alejandro R, Barton FB, Hering BJ, Wease S, Collaborative Islet Transplant Registry Investigators 2008 Update from the Collaborative Islet Transplant Registry. Transplantation. 2008;86:1783–8. doi: 10.1097/TP.0b013e3181913f6a. [DOI] [PubMed] [Google Scholar]
  • 7.Taub R. Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol. 2004;5:836–47. doi: 10.1038/nrm1489. [DOI] [PubMed] [Google Scholar]
  • 8.Michalopoulos GK. Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas. Am J Pathol. 2010;176:2–13. doi: 10.2353/ajpath.2010.090675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Sudo T, Hiyama E, Murakami Y, Yokoyama Y, Takesue Y, Sueda T. Hepatic regeneration promotes engraftment of intraportally transplanted islet cells. Surgery. 2005;137:612–9. doi: 10.1016/j.surg.2005.02.007. [DOI] [PubMed] [Google Scholar]
  • 10.Ding S, Merkulova-Rainon T, Han ZC, Tobelem G. HGF receptor up-regulation contributes to the angiogenic phenotype of human endothelial cells and promotes angiogenesis in vitro. Blood. 2003;101:4816–22. doi: 10.1182/blood-2002-06-1731. [DOI] [PubMed] [Google Scholar]
  • 11.Ferrara N, Chen H, Davis-Smyth T, Gerber HP, Nguyen TN, Peers D, et al. Vascular endothelial growth factor is essential for corpus luteum angiogenesis. Nat Med. 1998;4:336–40. doi: 10.1038/nm0398-336. [DOI] [PubMed] [Google Scholar]
  • 12.Fiaschi-Taesch NM, Berman DM, Sicari BM, Takane KK, Garcia-Ocaña A, Ricordi C, et al. Hepatocyte growth factor enhances engraftment and function of nonhuman primate islets. Diabetes. 2008;57:2745–54. doi: 10.2337/db08-1085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Nakano M, Yasunami Y, Maki T, Kodama S, Ikehara Y, Nakamura T, et al. Hepatocyte growth factor is essential for amelioration of hyperglycemia in streptozotocin-induced diabetic mice receiving a marginal mass of intrahepatic islet grafts. Transplantation. 2000;69:214–21. doi: 10.1097/00007890-200001270-00004. [DOI] [PubMed] [Google Scholar]
  • 14.Lee BW, Lee M, Chae HY, Lee S, Kang JG, Kim CS, et al. Effect of hypoxia-inducible VEGF gene expression on revascularization and graft function in mouse islet transplantation. Transpl Int. 2011;24:307–14. doi: 10.1111/j.1432-2277.2010.01194.x. [DOI] [PubMed] [Google Scholar]
  • 15.Golocheikine A, Tiriveedhi V, Angaswamy N, Benshoff N, Sabarinathan R, Mohanakumar T. Cooperative signaling for angiogenesis and neovascularization by VEGF and HGF following islet transplantation. Transplantation. 2010;90:725–31. doi: 10.1097/TP.0b013e3181ef8a63. [DOI] [PubMed] [Google Scholar]
  • 16.Zhang N, Richter A, Suriawinata J, Harbaran S, Altomonte J, Cong L, et al. Elevated vascular endothelial growth factor production in islets improves islet graft vascularization. Diabetes. 2004;53:963–70. doi: 10.2337/diabetes.53.4.963. [DOI] [PubMed] [Google Scholar]
  • 17.Yoshida D, Akahoshi T, Kawanaka H, Yamaguchi S, Kinjo N, Taketomi A, et al. Roles of vascular endothelial growth factor and endothelial nitric oxide synthase during revascularization and regeneration after partial hepatectomy in a rat model. Surg Today. 2011;41:1622–9. doi: 10.1007/s00595-010-4484-9. [DOI] [PubMed] [Google Scholar]
  • 18.Morsiani E, Fogli L, Rozga J, Ricci D, Azzena G, Demetriou AA. Growth of intraportally transplanted islets under liver regeneration stimulus and restoration of normoglycemia in streptozocin-diabetic rats. Surgery. 1998;123:398–406. doi: 10.1016/S0039-6060(98)70160-6. [DOI] [PubMed] [Google Scholar]
  • 19.Dunger A, Korsgren O, Andersson A. DNA replication in mouse pancreatic islets transplanted subcapsularly into the kidney or intraportally into the liver. Influence of unilateral nephrectomy or partial hepatectomy. Transplantation. 1990;49:686–9. doi: 10.1097/00007890-199004000-00006. [DOI] [PubMed] [Google Scholar]
  • 20.Low G, Hussein N, Owen RJ, Toso C, Patel VH, Bhargava R, et al. Role of imaging in clinical islet transplantation. Radiographics. 2010;30:353–66. doi: 10.1148/rg.302095741. [DOI] [PubMed] [Google Scholar]
  • 21.Ryan EA, Paty BW, Senior PA, Shapiro AM. Risks and side effects of islet transplantation. Curr Diab Rep. 2004;4:304–9. doi: 10.1007/s11892-004-0083-8. [DOI] [PubMed] [Google Scholar]
  • 22.Mittler J, McGillicuddy JW, Chavin KD. Laparoscopic liver resection in the treatment of hepatocellular carcinoma. Clin Liver Dis. 2011;15:371–84, vii-x. doi: 10.1016/j.cld.2011.03.009. [DOI] [PubMed] [Google Scholar]
  • 23.van Gulik TM, van den Esschert JW, de Graaf W, van Lienden KP, Busch OR, Heger M, et al. Controversies in the use of portal vein embolization. Dig Surg. 2008;25:436–44. doi: 10.1159/000184735. [DOI] [PubMed] [Google Scholar]
  • 24.Walsh TJ, Eggleston JC, Cameron JL. Portal hypertension, hepatic infarction, and liver failure complicating pancreatic islet autotransplantation. Surgery. 1982;91:485–7. [PubMed] [Google Scholar]
  • 25.Carlotti F, Zaldumbide A, Ellenbroek JH, Spijker HS, Hoeben RC, de Koning EJ. beta-Cell Generation: Can Rodent Studies Be Translated to Humans? J Transplant 2011; 2011:892453. [DOI] [PMC free article] [PubMed]
  • 26.Gotoh M, Maki T, Kiyoizumi T, Satomi S, Monaco AP. An improved method for isolation of mouse pancreatic islets. Transplantation. 1985;40:437–8. doi: 10.1097/00007890-198510000-00018. [DOI] [PubMed] [Google Scholar]
  • 27.Yonekawa Y, Okitsu T, Wake K, Iwanaga Y, Noguchi H, Nagata H, et al. A new mouse model for intraportal islet transplantation with limited hepatic lobe as a graft site. Transplantation. 2006;82:712–5. doi: 10.1097/01.tp.0000234906.29193.a6. [DOI] [PubMed] [Google Scholar]
  • 28.Miao G, Ostrowski RP, Mace J, Hough J, Hopper A, Peverini R, et al. Dynamic production of hypoxia-inducible factor-1alpha in early transplanted islets. Am J Transplant. 2006;6:2636–43. doi: 10.1111/j.1600-6143.2006.01541.x. [DOI] [PubMed] [Google Scholar]

Articles from Islets are provided here courtesy of Taylor & Francis

RESOURCES