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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 8 2471-2475
Copyright © 1997 by The Endocrine Society

Reproductive Endocrinology

Experimental Transplantation of Human Fetal and Adult Pancreatic Islets1

Alberto Hayek and Gillian M. Beattie

Department of Pediatrics, The Whittier Institute, University of California-San Diego School of Medicine, La Jolla, California 92037

Address all correspondence and requests for reprints to: A. Hayek, M.D., Department of Pediatrics, The Whittier Institute, 9894 Genesee Avenue, La Jolla, California 92037. E-mail ahayek{at}ucsd.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
We examined morphology and function following transplantation of human fetal islet-like clusters (ICCs) in nude mice and compared the functional efficiency of human adult islets and fetal ICCs after transplantation. To assess the optimal site we first transplanted ICCs under the kidney capsule, pancreas, lung, and liver in nude mice. Grafts to the kidney and pancreas matured functionally and morphologically, as evidenced by a 4-fold increase in C peptide after glucose stimulation and the presence of insulin in the grafts of all animals. Grafts to the lung, liver, and spleen did poorly; C peptide was only measurable in two of eight, two of five, or three of five of mice grafted to the lung, liver, or spleen, respectively. Using chemically diabetic nude rats as recipients, we were able to restore normoglycemia using 15,000 ICCs/kg. Lastly, when transplanted under the kidney capsule of normal nude mice, ICCs had significantly higher insulin contents and C peptide release than equivalent grafts of adult islets. In summary, ICCs are an efficient source of insulin-producing cells of potential use in clinical transplantation. In nude mice, both the kidney and the pancreas provide suitable environments for the growth and maturation of undifferentiated human ß-cells.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
TRANSPLANTATION of human adult islets as a therapy for insulin-dependent diabetes is limited not only by the paucity of cadaver-derived tissue, but also by the relatively poor clinical results using islet allografts (1). This makes human fetal islets or their precursor cells a potential alternative source of insulin-producing tissue for clinical transplantation (2). The success of transplanting fetal tissue is dependent on the ability of the fetal cells not only to grow, but also to mature at the implantation site. In humans, the optimal site for implantation of fetal pancreatic endocrine cells and, for that matter, of adult islets has yet to be determined. The present study was undertaken to evaluate the optimal site for growth and differentiation of human fetal pancreatic endocrine cells in athymic nude mice, and their ability to reverse diabetes in streptozocin (SZ)-diabetic athymic nude rats. Based on these results, we next compared the functional efficiency of human fetal endocrine tissue with that of adult islets after transplantation into nude mice.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Human tissue

The human fetal pancreases used in these experiments were provided by the Anatomic Gift Foundation (Laurel, MD) and Advanced Bioscience Resources (Oakland, CA) after the termination of pregnancy by dilatation and extraction between 18–24 weeks gestation. Gestational age was determined by several criteria, including biparietal diameter, femur length, and fetal foot measurement. Warm and cold ischemic times were approximately 5 min and 24 h, respectively. Informed consent for tissue donation was obtained by the procurement centers. In addition, our own institutional review board reviewed and approved the use of fetal tissue for these studies. For tissue culture the fetal pancreases were digested with collagenase and cultured as islet-like cell clusters (ICCs), as described previously (3, 4). The ICCs (100-µm average diameter) were hand selected under direct vision with a stereomicroscope. For the studies with fetal tissue, only ICCs were used because we have shown ICCs to be preferable to purified fetal islets or fresh fragments in transplantation experiments performed in nude mice (2).

Human adult islets were provided by the Diabetes Research Institute at the University of Miami (Miami, FL) and the Islet Isolation Core Facility at Washington University (St. Louis, MO). They were isolated with an automated method as described previously (5) and further purified by hand picking single islets (100-µm average diameter) after dithizone staining (6).

Quantification of cell numbers

Islets and ICCs were digested into single cells using nonenzymatic dissociating medium (Sigma Chemical Co., St. Louis, MO) as previously described (7). To estimate the number of cells per islet or ICC, single cell suspensions of 100 ICCs or adult islets were counted with a hemacytometer.

Transplant recipients

Animals used in these studies were 6-week-old male NIH Swiss homozygous athymic nude mice or Rowlett athymic nude rats obtained from the Charles River Breeding Laboratories (Charles River, MA). They were housed in microisolater cages in a semisterile room. Animals were maintained according to the NIH Guide for the Care and Use of Laboratory Animals.

Transplantation experiments

ICCs (500/animal) were transplanted into nude mice grouped according to the place of implantation: kidney, spleen, pancreas, lung, and liver (8, 9, 10). To aid in the localization of grafted tissue within the pancreatic parenchyma, blue agarose beads (Bio-Rad Laboratories, Richmond, CA) were added to the ICCs (10). For transplantation into the lung, the ICCs were embolized by injection into the external jugular vein (11) and into the liver by injection in the portal vein. After 3 months, the mice were fasted and given 3 g/kg glucose, ip. After 30 min, a blood sample was obtained for the measurement of human serum C peptide using a RIA that does not cross-react with mouse C peptide (Diagnostic Products Corp., Los Angeles, CA). Grafts were removed for histological analysis.

Diabetic rat studies

Because of the high mortality of nude mice after the induction of SZ diabetes and to test the effects of human cells in a larger animal, we selected 6-week-old nude rats, weighing 150–200 g. They were made diabetic by the administration of SZ (70 mg/kg, iv) at least 2 weeks before transplantation of 3,000 ICCs (from 1–2 fetal pancreases) under the kidney capsule. The number of ICCs (15,000/kg) was selected because we have shown that 500 ICCs were needed in nude mice weighing 6 times less (25 g) to generate a sufficient ß-cell mass to measure circulating human C peptide (12) and because rats are resistant to human insulin (9). In the same animal model, Korsgren and Jansson used approximately 4,500 porcine ICCs to cure diabetic nude rats (13). Only rats with blood glucose levels above 300 mg/dL after the SZ injections were used in these experiments. In some rats it was necessary to give more than 1 injection to achieve hyperglycemia. To avoid ketoacidosis, 2 U human insulin (NPH, Eli Lilly Co., Indianapolis, IN) were administered sc every 48 h until normoglycemia was achieved. Blood was withdrawn once weekly from the tail vein and 48 h after insulin injection to allow for complete disappearance of exogenous insulin. Glucose levels were determined with a portable glucose meter (One Touch, Lifescan, Inc., Milpitas, CA). After withdrawal of insulin treatment and at least 2 consecutive normal glucose measurements (<100 mg/dL), the kidney containing the graft was removed to document diabetes relapse.

Comparison of adult islet and fetal ICC grafts

Five hundred ICCs or adult islets were transplanted under the kidney capsule of nude mice (8, 9). Before implantation, an aliquot was removed for analysis of insulin and DNA contents. Three months after transplantation, fasted mice were challenged with glucose as described above. For analysis of insulin content, the grafted tissue was carefully peeled away from the kidney under direct vision. With the stereoscope it was possible to discern the difference between the kidney parenchyma and the grafted material, which was usually removed in one piece. After removal from the kidney, the transplanted tissue was minced finely, homogenized in distilled water, and sonicated. Insulin was assayed in acid-ethanol extracts of cell sonicates using a solid phase RIA (Diagnostic Products Corp.) as previously described (14). The DNA content of cell sonicates was measured using a fluorometric method (15).

Immunohistochemistry

Kidney, pancreas, and spleen were fixed in 4% paraformaldehyde, and sequential 5-µm sections were stained with hematoxylin and eosin and the immunoalkaline phosphatase technique (16), using guinea pig antiporcine insulin (Chemicon, El Segundo, CA) as the primary antibody. Normal rabbit serum was used as control serum. After death, lung parenchyma was perfused with dithizone to localize islet tissue as previously described (11) before fixation. Because of the difficulty of localizing grafted tissue in the liver, we extracted and measured the insulin content of grafted and control liver samples according to published protocols (17).

Statistical analysis

Data were analyzed by Student’s t test for unpaired data using StatView IV (Abacus Concepts, Berkeley, CA).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Comparison of transplantation sites

After glucose challenge 3 months following implantation, there was a parallel 4- to 5-fold response in animals receiving grafts under the kidney capsule or into the pancreas, as measured by serum human C peptide released in all animals in both groups. In contrast, circulating human C peptide was only detected in three of five animals receiving cells in the liver or spleen and in three of eight animals receiving cells in the lung. Additionally, the magnitude of the response was reduced to 2-fold in the mice receiving transplants in the liver or spleen. In only two mice receiving grafts to the lung were the human C peptide responses comparable to those of the mice with grafts to the kidney and pancreas (Table 1Go).


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  		Table 1. Serum C peptide (picomoles per L) in response to a glucose challenge in nude mice 3 months after transplantation

 
Immunohistological analyses of the grafts to the kidney and pancreas revealed areas of abundant endocrine tissue that were highly immunoreactive to insulin antibody (Fig. 1Go, A and B). In sections of lung that had previously stained with dithizone, only rare single islet-like structures were seen that were immunostained for insulin (Fig. 1CGo). Similarly in the spleen, only few areas of grafted tissue were seen, mostly ductal, and within these areas only rare cells were immunoreactive to insulin antibody (Fig. 1DGo).



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  		Figure 1. Representative photomicrographs of ICCs grafted to the kidney (A), pancreas (B), lung (C), and spleen (D) of nude mice 3 months after transplantation. Sections were immunostained by the alkaline phosphatase method, with guinea pig antiporcine insulin as the primary antibody. Insulin staining can be seen as dark pigment. Note the abundance of insulin-containing cells in the kidney (A) and pancreas (B) where the grafted tissue lies adjacent to an agarose blue bead (arrow). In the spleen the endocrine cells are surrounded by fibrous tissue (arrowheads; D). Actual magnification, x750.

 
The total insulin content of the livers that had successful transplants, as determined by the detectable human serum C peptide response to glucose challenge, were 36, 239, and 283 pmol, respectively.

Reversal of diabetes in nude rats

Six diabetic rats were used in these experiments. One animal died 2 weeks after transplantation with blood glucose values over 500 mg/dL. The remaining rats were hyperglycemic for 9–10 weeks following transplantation. At that time there was a sudden drop in the normal glucose values that remained after exogenous insulin was withdrawn. This lag period corresponds to the amount of time needed for the undifferentiated ß-cells in ICCs to become glucose responsive (12). The weight of all rats had increased to more than 300 g. After removal of the kidney containing the graft, all animals reverted to the diabetic state (Fig. 2Go)



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  		Figure 2. Blood glucose levels of SZ-diabetic rats after transplantation of 3000 ICCs under the kidney capsule. Blood was withdrawn once weekly from the tail vein, and glucose levels were determined with a portable glucose meter.

 
Comparison of adult islet and fetal ICCs

In these studies, ICCs and adult islets of similar diameter were used for comparison. Cell numbers and DNA content were also comparable [369 ± 44 cells/ICC and 311 ± 20 cells/islet (n = 10; P = NS); 22.8 ± 6.4 ng DNA/ICC and 29 ± 5.8 ng DNA/islet (n = 5; P = NS)]. Transplanted ICCs, initially low in insulin, gave rise to grafts that had significantly higher levels of insulin than those from the same number of adult islets (1.17 ± 0.3 pmol insulin/ICC grafted vs. 0.54 ± 0.06 pmol insulin/islet grafted; P < 0.05; n = 5; Fig. 3AGo). In fact, insulin levels in each of the grafts of adult islets were significantly decreased from the pretransplant levels (1.148 pmol insulin/islet pretransplant vs. 0.54 ± 0.06 pmol/islet posttransplant; P < 0.05; n = 5; Fig. 3AGo). Stimulated serum C peptide levels were significantly higher in mice bearing the ICC grafts than in those with the adult islet grafts (1295 ± 96 vs. 698 ± 96 pmol C peptide/L; n = 5; P < 0.05; Fig. 3BGo).



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  		Figure 3. Comparison of human adult islets and fetal ICCs before and 3 months after grafting under the kidney capsule of nude mice. A, Insulin contents of acid-ethanol extracts of adult islets or fetal ICCs were determined by RIA before and 3 months after transplantation under the kidney capsule of nude mice (n = 5; *, P < 0.05 compared to ICCs posttransplant and to islets pretransplant; ***, P < 0.001 compared to ICCs pretransplant). B, Three months after transplantation, circulating human C peptide levels were measured before and after glucose challenge in fasted nude mice grafted with 500 islets or 500 ICCs (n = 5; P < 0.05 compared to ICCs).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
From these studies we may conclude that 1) the recipient organ has a significant influence in the eventual outcome of a cell transplant; 2) ICCs transplanted under the kidney capsule reverse diabetes in the SZ-diabetic nude rat; and 3) under similar transplant conditions, ICCs are a richer source of insulin-producing tissue than a comparable mass of adult islets.

Considerations involved in the choice of organ for islet transplantation include the facility of transplantation, the capability of revascularization, the issue of insulin drainage to the hepatic system or the systemic circulation, and the availability of specific cytokines required for growth and maturation of ß-cells in the case of undifferentiated cells. In previous studies the kidney capsule has been the preferred site for transplanting human fetal pancreas in athymic nude mice (18, 19, 20, 21, 22). Using uncultured human fetal pancreas, Tuch et al. compared the sc site to the kidney capsule and found the latter to be superior (23). Recently, Korsgren and Jansson showed that porcine ICCs cure diabetic nude rats when transplanted under the kidney capsule, but not when implanted into the liver or spleen (13). In a syngeneic system implanting newborn islets into diabetic rats, we found no difference in the metabolic responses of grafts to the spleen or kidney, both sites preferable to the omentum (8). Extending these studies, we have shown that pancreas (10) and lung (11) are also efficacious sites.

The present study shows that human fetal endocrine tissue in the form of ICCs was able to mature functionally and morphologically when grafted to the kidney or pancreas in normoglycemic nude mice. This is evidenced by a 4-fold increase in circulating human C peptide and the presence of immunoreactive insulin in the grafts in all animals in both groups. In contrast, circulating human C peptide was measurable in only three of eight animals transplanted to the lung, and only two of these animals had responses comparable to those in animals grafted to pancreas or kidney. Human C peptide was only detected in three of five mice transplanted to the spleen or liver.

In addition to the functional and morphological maturation, we were able to demonstrate successful amelioration of hyperglycemia in all diabetic rats transplanted with 15,000 ICCs/kg under the kidney capsule, suggesting that ICCs could be useful in clinical transplantation protocols, providing adequate immunosuppression is available. In direct comparisons after transplantation of adult islets and fetal ICCs, we were able to show that grafts had significantly higher insulin content and human C peptide levels after glucose challenges than grafts of equivalent numbers of adult islets. Our data showing loss of insulin from adult islets posttransplantation are in accordance with the recent finding that there is a general vulnerability of adult islets in the immediate posttransplantation period (24) and a selective loss of ß-cells after transplantation of adult human islets in nude mice (25). From our data here and in previous reports (26), it appears unlikely that this loss occurs in the undifferentiated ß-cells contained in ICCs with the potential to mature after transplantation.

Together, these studies show that human fetal ICCs are an efficient source of insulin-producing tissue for replacement in insulin-deficient states. In nude mice, both kidney and pancreas provide a suitable environment for the growth and maturation of undifferentiated ß-cells.


   Acknowledgments
 
We thank Ana D. Lopez for excellent technical assistance.


   Footnotes
 
1 This work was supported by Juvenile Diabetes Foundation Grant 195041 and the Herbert O. Perry Fund. Back

Received February 13, 1997.

Revised April 1, 1997.

Accepted April 21, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Robertson RP. 1992 Pancreatic and islet transplantation for diabetes–cures or curiosities? N Engl J Med. 327:1861–1868.[Medline]
  2. Beattie GM, Otonkoski T, Lopez AD, Hayek A. 1997 Functional ß-cell mass after transplantation of human fetal pancreatic cells: differentiation or proliferation? Diabetes. 46:244–248.[Abstract]
  3. Beattie GM, Otonkoski T, Lopez AD, Hayek A. 1993 Maturation and function of human fetal pancreatic cells after cryopreservation. Transplantation. 56:1340–1343.[Medline]
  4. Beattie GM, Levine F, Mally M, et al. 1994 Acid ß-galactosidase: a developmentally regulated marker of endocrine cell precursors in the human fetal pancreas. J Clin Endocrinol Metab. 78:1232–1240.[Abstract]
  5. Ricordi C, Lacy PE, Finke EH, Olack BJ, Scharp DW. 1988 Automated method for isolation of human pancreatic islets. Diabetes. 37:413–420.[Abstract]
  6. Latif ZA, Noel J, Alejandro R. 1988 A simple method of staining fresh and cultured islets. Transplantation. 45:827–830.[Medline]
  7. Beattie GM, Rubin JS, Mally MI, Otonkoski T, Hayek A. 1996 Regulation of proliferation and differentiation of human fetal pancreatic islet cells by extracellular matrix, hepatocyte growth factor and cell-cell contact. Diabetes. 45:1223–1228.[Abstract]
  8. Hayek A, Lopez AD, Beattie GM. 1990 Factors influencing islet transplantation–number, location, and metabolic control. Transplantation. 49:224–225.[Medline]
  9. Hayek A, Lopez AD, Beattie GM. 1988 Decrease in the number of neonatal islets required for successful transplantation by strict metabolic control of diabetic rats. Transplantation. 45:940–942.[Medline]
  10. Hayek A, Beattie GM. 1992 Intrapancreatic islet transplantation in experimental diabetes in the rat. Metabolism. 41:1367–1369.[Medline]
  11. Hayek A, Beattie GM. 1992 Reversal of experimental diabetes by injection of syngeneic islets into peripheral veins. Cell Transplant. 1:83–85.[Medline]
  12. Beattie GM, Butler C, Hayek A. 1994 Morphology and function of cultured human fetal pancreatic cells transplanted into athymic mice: a longitudinal study. Cell Transplant. 3:421–425.[Medline]
  13. Korsgren O, Jansson L. 1994 Porcine islet-like cell clusters cure diabetic nude rats when transplanted under the kidney capsule, but not when implanted into the liver or spleen. Cell Transplant. 3:49–54.[Medline]
  14. Otonkoski T, Beattie GM, Mally MI, Ricordi C, Hayek A. 1993 Nicotinamide is a potent inducer of endocrine differentiation in cultured human fetal pancreatic cells. J Clin Invest. 92:1459–1466.
  15. Hinegardner RT. 1971 An improved fluorometric assay for DNA. Anal Biochem. 39:197–201.[CrossRef][Medline]
  16. Erber WN, Mason DY. 1987 Immunoalkaline phosphatase labeling of terminal transferase in hematologic samples. Am J Clin Pathol. 88:43–50.[Medline]
  17. Gray DWR, McShane P, Morris PJ. 1986 Islets transplanted to the kidney capsule site. Transplantation. 41:699–703.[Medline]
  18. Tuch BE, Ng ABP, Jones A, Turtle JR. 1984 Histologic differentiation of human fetal pancreatic explants transplanted into nude mice. Diabetes. 33:1180–1187.[Abstract]
  19. Tuch BE, Monk RS. 1991 Regulation of blood glucose to human levels by human fetal pancreatic xenografts. Transplantation. 51:1156–1160.[Medline]
  20. Tuch BE. 1991 Reversal of diabetes by human fetal pancreas. Transplantation. 51:557–562.[Medline]
  21. Hullett DA, Bethke KP, Landry AS, Leonard DK, Sollinger HW. 1989 Successful long-term cryopreservation and transplantation of human fetal pancreas. Diabetes. 38:448–453.[Abstract]
  22. Sandler S, Andersson A, Schnell A, et al. 1985 Tissue culture of human fetal pancreas. Development and function of b-cells in vitro and transplantation of explants to nude mice. Diabetes. 34:1113–1119.[Abstract]
  23. Tuch BE, Grigoriou S, Turtle JR. 1986 Growth and hormonal content of human fetal pancreas passaged in athymic mice. Diabetes. 35:464–469.[Abstract]
  24. Davalli AM, Seaglia L, Zangen DH, Hollister J, Bonner-Weir S, Weir GC. 1996 Vulnerability of islets in the immediate posttransplantation period. Diabetes. 45:1161–1167.[Abstract]
  25. Davalli AM, Ogawa Y, Ricordi C, Scharp DW, Bonner-Weir S, Weir GC. 1995 A selective decrease in the beta cell mass of human islets transplanted into diabetic nude mice. Transplantation. 59:817–820.[Medline]
  26. Beattie GM, Crowe JH, Lopez AD, Cirulli V, Ricordi C, Hayek A. 1997 Trehalose: a cryoprotectant that enhances recovery and preserves function of human pancreatic islets after long-term storage. Diabetes. 46:519–524.[Abstract]



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