Transplantation of Human Fetal Pancreas: Experience in Thymusaplastic Mice and Rats and in a Diabetic Patient

Usadel, K.H.; Schwedes, U.; Bastert, G.; U, Steinau; Klempa, I; Fassbinder, W; Schöffling, Κ.

doi:10.2337/diab.29.1.s74

Cited by 27 publications

(15 citation statements)

References 5 publications

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“…Moreover, when grafted into immunodeficient mice, human pancreas at 6-16 WD keeps its ability to develop into a functional endocrine tissue (Usadel et al 1980, Lafferty & Hao 1993, Beattie et al 1997, Castaing et al 2001. Peripheral mesenchyme and/or its secreted factors seem to have a stimulating effect on the proliferation of the neighboring epithelial cells, as we found peripheral ducts to proliferate 2-3 times more than the central ones (Polak et al 2000).…”

Section: Introductionmentioning

confidence: 50%

A transient microenvironment loaded mainly with macrophages in the early developing human pancreas

Banaei-Bouchareb

Peuchmaur²,

Czernichow³

et al. 2006

Journal of Endocrinology

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We have previously shown that the human developing pancreas, as a tissue under construction and remodeling, is composed of epithelial ducts and differentiated endocrine cells surrounded by mesenchyme. The physiologic importance of resident tissue leukocytes, expected to enter through the mesenchyme in remodeling functions, prompted us to investigate human developing pancreases for the presence of leukocyte lineages and for expression of cytokines and receptors involved in their recruitment and differentiation. Immunohistochemistry studies were performed on 69 human, paraffin-embedded pancreases at 6-12 weeks of development (WD). Cytokines and receptor transcripts were monitored by reverse transcription (RT)-PCR, by immunohistochemistry when antibodies were available or by in situ hybridization (ISH). We show that numerous cells expressing CD45RA, HLADR and CD68 antigens are cellular components of the mesenchyme of all the pancreases at 6-12 WD. So-called constitutive chemokines (SLC (CCL19), stromal-derived factor 1 (SDF1) (CXCL12)) and a macrophage-specific growth/ survival factor, colony-stimulating factor 1 (CSF1), were detected in epithelial duct cells. Both epithelial and mesenchymal cells expressed chemokine receptors, suggesting a role in leukocyte recruitment and possibly in early pancreatic development. In conclusion, we demonstrated the presence of CD45RA resident leukocytederived lineages, mostly macrophages, in the early human pancreatic mesenchyme. These cells may have migrated in the tissue through the vascular system, attracted by constitutively expressed chemokines, and locally surviving through CSF1 signaling. The role of macrophages in epithelium/mesenchyme interaction-mediated pancreatic development remains to be demonstrated.

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Section: Introductionmentioning

confidence: 50%

A transient microenvironment loaded mainly with macrophages in the early developing human pancreas

Banaei-Bouchareb

Peuchmaur²,

Czernichow³

et al. 2006

Journal of Endocrinology

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“…During the time it takes to normalize blood glucose levels, the fetal pancreatic tissue differentiates and proliferates [Tuch et al, 1984]. Precursor duct cells differentiate into endocrine cells, especially ß cells, by a process termed nesidioblastosis [Pictet and Rutter, 1972], with islets forming [Usadel et al, 1980;Hullett et al, 1987], and the percentage of ß cells in the graft increasing [Tuch et al, 1986;Beattie et al, 1994]. Morphologically, at the time the tissue is transplanted, endocrine tissue is in the minority, but 3 months after transplantation, the proportion of ß cells has increased to such an extent that they are the predominant cell type in the graft [Beattie et al, 1994].…”

Section: Introductionmentioning

confidence: 99%

Development of Human Fetal Pancreas after Transplantation into SCID Mice

Tuch²,

Walsh³

2001

Cells Tissues Organs

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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.

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“…Indeed, we have recently found evidence for tissue specific islet antigens, demonstrable in vitro (25), and the immunogenicity of these islet antigens may be amplified by currently used enzymatic isolation techniques. Whereas attempts to transplant islets in the human in an allogeneic setting have been routinely unsuccessful (26)(27)(28)(29), a technique employing intraperitoneal transplantation of a vascularized, FDPS has been used clin- 298 Kyriakides, Rabinovitch, Mintz, Olson, Rapaport, and Miller ically in 13 patients by Sutherland et al (30,31), with term graft survival was possible (7-9). However, a few technical problems and with encouraging results.…”

Section: Methodsmentioning

confidence: 99%

Long-Term Study of Vascularized Free-Draining Intraperitoneal Pancreatic Segmental Allografts in Beagle Dogs

Kyriakides¹,

Rabinovitch²,

Mintz³

et al. 1981

J. Clin. Invest.

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A B S T R A C T The purpose of the present study was to evaluate the significance of immunogenetic factors on the survival of pancreatic allografts in beagle dogs. Donors and recipients were leukocyte antigen (DLA)-typed and mixed lymphocyte culture (MLC)-tested. Recipients were made diabetic by total pancreatectomy and immediately implanted intraperitoneally with a vascularized, free-draining (duct unligated) pancreatic segmental (FDPS) allograft. Two groups of dogs were studied. In group I consisting of donor-recipient littermates, recipients were immunosuppressed with prednisone and azathioprine (n = 16 dogs), or not immunosuppressed (n = 4). In group II, recipients were made specifically unresponsive by total body radiation, autologous marrow implantation, and kidney transplantation from DLA-MLC identical donors, 1 yr before FDPS transplantation from the corresponding original kidney donors.Survival of the FDPS grafts in group I was inversely related to pretransplant MLC reactivity, irrespective of DLA genotyped match between donor and recipient. Thus, immunosuppressed high MLC reactors (n = 8) rejected FDPS grafts between 7 and 14 d, whereas immunosuppressed low MLC reactors (n = 8) accepted grafts for 25 to 260+ days, and nonimmunosuppressed low MLC reactors (n = 4) accepted grafts for 9-55 d. Rejection (hyperglycemia) of FDPS grafts was sudden, permanent, and unpredictable despite weekly intravenous glucose tolerance tests with measurements of glucose disappearance rates and serum insulin responses. Nevertheless, serial in vitro cell-mediated

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Transplantation of Human Fetal Pancreas: Experience in Thymusaplastic Mice and Rats and in a Diabetic Patient

Cited by 27 publications

References 5 publications

A transient microenvironment loaded mainly with macrophages in the early developing human pancreas

A transient microenvironment loaded mainly with macrophages in the early developing human pancreas

Development of Human Fetal Pancreas after Transplantation into SCID Mice

Long-Term Study of Vascularized Free-Draining Intraperitoneal Pancreatic Segmental Allografts in Beagle Dogs

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