Development of Human Fetal Pancreas after Transplantation into SCID Mice

Abstract

Only a small component of human fetal pancreas consists of β cells, and yet this tissue is capable of normalizing the blood glucose levels of diabetic recipients when transplanted. The time taken to achieve this goal is several months, during which time the tissue proliferates and eventually differentiates into β cells. The dynamics of β cell development have not been described previously. We transplanted human fetal pancreas beneath the renal capsule of immunodeficient mice and analysed the grafts for a period of 12 weeks using antibodies against exocrine cells (lipase), endocrine cells and protodifferentiated duct cells. Exocrine cells constituted 48% of all epithelial cells in the untransplanted pancreas, with duct cells comprising 29% and endocrine cells 16% (β cells 7%). The percentage of exocrine cells declined with time after transplantation, with only a small number undergoing apoptosis, and the duct cells increased, the values for these two cell types at 12 weeks being 20 and 57%, respectively. Both cell types appeared to proliferate equally for up to 8 weeks after transplantation, but only duct cells thereafter. Endocrine cells began to increase from 8 weeks after transplantation, representing 28% of epithelial cells (β cells 11%) at this time. Intermediate cells, that is, cells expressing the characteristics of more than one type of mature pancreatic cell, were observed both in the ungrafted pancreas and after transplantation. The commonest intermediate cell type was duct/exocrine, with exocrine/endocrine and duct/endocrine cells also observed, suggesting active transdifferentiation from one cell type to another. We hypothesize that following the transplantation of human fetal pancreatic tissue, exocrine cells mostly transdifferentiate into duct cells and these eventually develop into endocrine cells, in particular β cells.

Reduced Immunogenicity of First-Trimester Human Fetal Pancreas

“…To examine the immunogenicity of first-trimester human fetal pancreas, a humanized mouse model was established. We determined that the optimal number of human PBMCs to achieve engraftment in NOD/SCID mice was 5 ϫ 10 7 and that second-trimester human fetal pancreas, which is known to be immunogenic, was rejected after 3 weeks when transplanted in this model (data not shown).…”

“…Furthermore, after transplantation into diabetic immunoincompetent rodents, the tissue consistently differentiates into a functionally mature graft (2-6) containing ␤-cells and other endocrine cells (7) and is able to normalize blood glucose levels (BGLs) in diabetic rodents (2,3,5,6). Another advantage of transplanting fetal tissue is its possible immune privileged status, as has been demonstrated for other fetal tissue transplants (8 -11).…”

Transplantation of differentiated umbilical cord mesenchymal cells under kidney capsule for control of type I diabetes in rat

“…Portal vein, liver (Pepper et al, 2013;Carlsson et al, 2001), spleen (Gray, 1990), omentum, pancreas, muscle, gastric sub mucosa, subcutaneous, genitourinary tract, anterior eye chamber, thymus and testis are the suggested sites for animal islet transplantation (Cantarelli and Piemonti, 2011;Rajab, 2010). Renal sub capsular space can provide a better condition for transplanted islet cells (Mellgren et al, 1986;Si et al, 2001;Hawthorne et al, 2011) and it is the most widely used site in rodents (Pepper et al, 2013). Also, in human it was reported that kidney, liver, muscle, and omentum are respectively the best sites for islet transplantation (Kim et al, 2010).…”

Comparison of Size, Viability, and Function of Fetal Pig Islet-Like Cell Clusters after Digestion Using Collagenase or Liberase

“…The activity of Viability With Fluorescent Dyes collagenase in the two preparations was 3.15 and 3. 26 Viability of ICCs was tested using the fluorescent Wunsch U/mg, respectively. dyes, carboxyfluorescein diacetate (6-CFDA) and pro-The buffer used to dissolve collagenase was Dulbecpidium iodide (PI).…”