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Biomedical subjects

Marc R Hammerman

Publications and source records attributed to Marc R Hammerman.

At least 19 recordsLinked to original sources
PubMed2006

Glucose tolerance normalization following transplantation of pig pancreatic primordia into non-immunosuppressed diabetic ZDF rats.

Pancreas or pancreatic islet transplantation in humans is limited by organ availability, and success of the latter is negatively impacted upon by tissue loss post-transplantation and limited potential for expansion of beta cells. A way to overcome the supply and expansion problems is to xenotransplant embryonic tissue. Previously, we have shown that beta cells originating from embryonic day (E) 28 (E28) pig pancreatic primordia transplanted into the mesentery of streptozotocin-diabetic (type 1) Lewis rats engraft without the need for host immune-suppression and normalize glucose tolerance. Here we show long-term engraftment of pig beta cells within liver, pancreas and mesenteric lymph nodes post-transplantation of E28 pig pancreatic primordia into diabetic ZDF rats, a model for type 2 diabetes. Porcine insulin is present in circulation after an oral glucose load. Glucose tolerance is normalized in transplanted ZDF hosts and insulin sensitivity restored in formerly diabetic ZDF males. Release of porcine insulin in vitro from tissue originating in transplanted rats occurs within 1 min of glucose stimulation characteristic of first-phase secretion from beta cells. Of potential importance for application of this transplantation technology to treatment of type 2 diabetes in humans and confirmatory of our previous findings in Lewis rats, no host immunosuppression is required for engraftment of E28 pig pancreatic primordia.

Animals↗
PubMed2006

Growing new endocrine pancreas in situ.

Type 1 diabetes mellitus is a major cause of endstage renal disease in young adults. Maintenance of normoglycemia in type 1 diabetics using exogenous insulin is difficult under the best of circumstances. Transplantation therapies are limited by the scarcity of human donor organs, rendering a priority the identification of an alternative source for replacing insulin-secreting cells. Embryonic pancreatic primordia transplanted into diabetic animal hosts undergo selective endocrine differentiation in situ and normalize glucose tolerance. Pancreatic primordia can be transplanted across isogeneic, allogeneic, and both concordant (rat-to-mouse) and highly disparate (pig-to-rodent) xenogeneic barriers. Successful transplantation of pancreatic primordia depends on obtaining them at defined windows during embryonic development within which the risk of teratogenicity is eliminated, growth potential is maximized, and immunogenicity is reduced. Here we review studies exploring the potential for pancreatic organogenesis post-transplantation of embryonic primordia as a therapy for type 1 diabetes.

Animals↗
PubMed2006

Cellular therapies for kidney failure.

Dialysis and transplantation of human kidneys represent effective therapies to replace kidney function, but each has limitations. Xenotransplantation of whole kidneys from non-primate donors is complicated by humoral and severe cellular rejection. The use of individual cells or groups of cells to regenerate or repair damaged tissue (cellular therapies) offers an alternative for renal replacement. Cellular strategies include: incorporation of new nephrons into the kidney; growing new kidneys in situ/renal organogenesis; use of embryonic or adult stem cells; and nuclear transplantation/therapeutic cloning. These approaches circumvent humoral rejection of xenogeneic tissue. Cellular rejection is ameliorated if embryonic cells are transplanted. It is likely that replacement of renal function via one or more cellular approach will constitute a part of future mainstream medical practice.

Animals↗
PubMed2005

Differential origin for endothelial and mesangial cells after transplantation of pig fetal renal primordia into rats.

Xenotransplantation of renal primordia in lieu of human kidney allografts has been proposed as a solution for the lack of organ availability. We and others have shown that growth and development of pig renal primordia occur post-transplantation across a highly disparate xenogenic barrier to rat. The origins (donor versus host) of endothelial cells (ECs) and mesangial cells (MCs) in grafts are incompletely delineated. In the present study, we investigated using immunohistochemistry, the origin ECs and MCs of the metanephric xenografts originating from embryonic day 28 (E28) pig embryos transplanted into rats. We employed species-specific antibodies: anti-rat endothelial cell antigen-1 (RECA-1) and -CD31 to detect rat- and pig-derived ECs, respectively; and anti-Thy-1 and -vimentin to detect rat- and pig-derived MCs, respectively. Both intra- and extraglomerular ECs in the xenografts were stained exclusively with rat-specific anti-RECA-1 at 5, 7, or 8 weeks post-transplantation, whereas ECs were not stained with pig-specific anti-CD31. In contrast, MCs in the xenografts were stained predominantly using the pig specific anti-vimentin, although a few glomeruli were positive for rat-specific anti-Thy-1. We conclude that the predominant origin of ECs post-transplantation of embryonic pig metanephroi into rats is the host, whereas MCs originate mainly from the donor.

Animals↗
PubMed2005

Normalization of glucose post-transplantation of pig pancreatic anlagen into non-immunosuppressed diabetic rats depends on obtaining anlagen prior to embryonic day 35.

Embryonic day (E) 28 (E28) pig pancreatic anlagen (PPA) transplanted into the omentum of non-immunosuppressed steptozotocin-diabetic Lewis rats normalize levels of circulating glucose within 2-4 weeks. Following transplantation formerly diabetic rats have porcine insulin, but no rat insulin detectable in circulation. At 3 weeks post-E28 PPA transplantation, bits of insulin-positive tissue are observed amidst host omental fat, but by 6 weeks only individual alpha and beta cells remain. In contrast, E35 PPA transplantation does not normalize glucose and 6 weeks post-implantation of E35 PPA transplanted tissue is rejected. In contrast to E28 PPA, no trace of implanted renal tissue is detectable post implantation of E28 pig renal anlagen (PRA) in non-immunosuppressed non-diabetic rats or in streptozocin-diabetic rats previously transplanted with E28 PPA. In the latter, normoglycemia is maintained post-PRA transplantation. We conclude that normalization of glucose levels following transplantation of PPA into non-immunosuppressed Lewis rats depends on obtaining the anlagen before E35 and that prior successful engraftment of E28 PPA as reflected by normalization of glucose, does not permit successful engraftment of E28 PRA.

Animals↗
PubMed2005

Windows of opportunity for organogenesis.

Growing new organs in situ by implanting developing animal organ anlagen/primordia represents a novel solution to the problem of limited supply for human donor organs that offers advantages relative to transplanting embryonic stem (ES) cells or xenotransplantation of developed organs. We and others have shown that renal anlagen transplanted into animal hosts undergo differentiation and growth, become vascularized by blood vessels of host origin, exhibit excretory function and support life in otherwise anephric hosts. Renal anlagen can be transplanted across both concordant (rat to mouse) and highly disparate (pig to rodent) xenogeneic barriers. Similarly, pancreatic anlagen can be transplanted across concordant and highly disparate barriers, and undergo growth, differentiation and secrete insulin in a physiological manner following intra-peritoneal placement. Successful transplantation of organ primordia depends on obtaining them at defined windows during embryonic development within which the risk of teratogenicity is eliminated, growth potential is maximized, and immunogenicity is reduced. Here we review studies that delineate such developmental windows of opportunity for kidney and pancreas.

Animals↗
PubMed2005

Cellular transplantation of nephrons.

Cellular transplantation of nephrons. Embryonic renal cellular primordia transplanted into animal hosts undergo nephrogenesis in situ, become vascularized by blood vessels of host origin, exhibit excretory function, and support life in otherwise anephric hosts. Renal primordia can be transplanted across isogeneic, allogeneic, and both concordant (rat to mouse) and highly disparate (pig to rodent) xenogeneic barriers. Here I review studies exploring the therapeutic potential for renal organogenesis posttransplantation of cellular kidney primordia.

Animals↗
PubMed2005

Organogenesis of the endocrine pancreas.

Organogenesis of the endocrine pancreas. Embryonic pancreatic primordia transplanted into diabetic animal hosts undergo selective endocrine differentiation in situ and normalize glucose tolerance. Pancreatic primordia can be transplanted across isogeneic, allogeneic, and both concordant (rat to mouse) and highly disparate (pig to rodent) xenogeneic barriers. This review explores the therapeutic potential for pancreatic organogenesis posttransplantation of embryonic primordia.

Animals↗
PubMed2004

Growing new kidneys in situ.

One novel solution to the shortage of human organs available for transplantation envisions "growing" new organs in situ via xenotransplantation of developing primordia from animal embryos. Renal primordia (metanephroi) transplanted into animal hosts undergo organogenesis in situ, become vascularized by blood vessels of host origin, and exhibit excretory function. Metanephroi can be stored in vitro prior to transplantation and can be transplanted across both concordant (rat-to-mouse) and highly disparate (pig-to-rodent) xenogeneic barriers. Here we review studies exploring the therapeutic potential for renal organogenesis post-transplantation of kidney primordia.

Animals↗
PubMed2004

Treatment for end-stage renal disease: an organogenesis/tissue engineering odyssey.

The means by which kidney function can be replaced in humans with end-stage renal disease (ESRD) include dialytic therapies and renal allotransplantation. Dialysis, is lifesaving, but often poorly tolerated. Transplantation of human kidneys is limited by the availability of donor organs. During the past decades, several different approaches have been applied towards new means to replace renal function through organogenesis and tissue engineering. These include: (1) incorporation of new nephrons into the kidney; (2) growing new kidneys in situ; (3) use of stem cells; (4) generation of histocompatible tissues using nuclear transplantation; and (5) bioengineering of an artificial kidney. The development of these approaches has depended upon understanding and integrating discoveries made in a diversity of scientific disciplines. The means by which such integration has driven advances in the treatment of ESRD provides a generic roadmap for the successful application of organogenesis and tissue engineering to organ replacement therapy.

Cloning, Organism↗
PubMed2004

Organogenesis of kidneys following transplantation of renal progenitor cells.

One novel solution to the shortage of human organs available for transplantation envisions 'growing' new organs in situ via xenotransplantation of developing anlagen from animal embryos. We and others have shown that renal progenitor cells (metanephroi) transplanted into animal hosts undergo organogenesis (differentiation and growth), become vascularized by blood vessels of host origin and exhibit excretory function. Metanephroi can be stored for up to 3 days in vitro prior to transplantation with no impairment in growth or function post-implantation. Metanephroi can be transplanted across both concordant (rat to mouse) and highly disparate (pig to rodent) xenogeneic barriers. Here we review studies exploring the potential therapeutic use of embryonic kidney transplantation as a means to achieve renal organogenesis.

Animals↗
PubMed2004

Organogenesis of endocrine pancreas from transplanted embryonic anlagen.

The number of donor human pancreas organs that can be transplanted directly or used for islet of Langerhans isolation is limited. We and others have shown that it is possible to 'grow' new pancreatic tissue in situ by transplanting embryonic organ-specific pancreatic precursor cells. This technology takes advantage of the fact that selective development of islets takes place post transplantation of embryonic pancreas and that the developing organ can attract its blood supply from an appropriate vascular bed post transplantation, enabling the transplantation of pancreas in 'cellular' form. Whole pancreatic anlagen implanted into a host peritoneum develop into a novel organ consisting of functional islets of Langerhans surrounded by stroma or individual alpha and beta cells within omental fat. Transplantation of developing pancreas to achieve organogenesis of its endocrine components could lead to a novel treatment for diabetes mellitus.

Animals↗
PubMed2004

Applications of organ precursor cell therapy: can lessons from embryonic kidney transplantation be applied to the endocrine pancreas?

PURPOSE OF REVIEW: The purpose of this review is to provide an update relating to a novel approach to endocrine pancreas replacement therapy based in part on a technology developed for the transplantation of developing kidneys. The approach is to use organ primordia, and in this way transplant kidneys or pancreas in cellular form. RECENT FINDINGS: Cellular allotransplantation and xenotransplantation of both kidney and pancreatic anlagen has been successfully performed such that functioning organs develop in situ. SUMMARY: The number of human organs available for transplantation is limited. We and others have shown that it is possible to 'grow' new kidneys or endocrine pancreas from organ-specific precursor cells in situ. For the kidney, this technology takes advantage of the fact that a developing renal anlagen can attract its blood supply from an appropriate vascular bed post-transplantation, enabling the transplantation of kidneys in 'cellular' form. Techniques developed for the transplantation of embryonic kidneys can be applied to the transplantation of embryonic pancreas. Pancreatic anlagen implanted into a host peritoneum develop into a novel organ consisting of functional islets of Langerhans surrounded by stroma. The transplantation of developing pancreas could represent a novel 'cellular' treatment for diabetes mellitus, a major cause of end-stage renal disease.

Animals↗
PubMed2004

Renal organogenesis from transplanted metanephric primordia.

One novel solution to the shortage of human organs available for transplantation envisions growing new organs in situ via xenotransplantation of developing primordia from animal embryos. It has been shown that renal primordia (metanephroi) transplanted into animal hosts undergo organogenesis in situ, become vascularized by blood vessels of host origin, and exhibit excretory function. Metanephroi can be stored for up to 3 d in vitro before transplantation with no impairment in growth or function post-implantation. Metanephroi can be transplanted across both concordant (rat to mouse) and highly disparate (pig to rodent) xenogeneic barriers. This is a review of studies exploring the therapeutic potential for renal organogenesis posttransplantation of kidney primordia.

Animals↗
PubMed2004

Transplantation of embryonic organs - kidney and pancreas.

One novel solution to the shortage of human organs available for transplantation envisions 'growing' new organs in situ via xenotransplantation of developing anlagen from animal embryos. We and others have shown that renal anlagen (metanephroi) transplanted into animal hosts undergo differentiation and growth, become vascularized by blood vessels of host origin and exhibit excretory function. Metanephroi can be stored for up to 3 days in vitro prior to transplantation with no impairment in growth or function post-implantation. Metanephroi can be transplanted across both concordant (rat to mouse) and highly disparate (pig to rodent) xenogeneic barriers. Similarly, pancreatic anlagen undergo growth, differentiation and secrete insulin in a physiological manner following intraperitoneal placement. Implantation of the embryonic pancreas, is followed by selective differentiation of islet as compared to acinar components. Here we review studies exploring the potential therapeutic use of embryonic kidney or pancreas transplantation.

Animals↗
PubMed2003

Islet cell engraftment and control of diabetes in rats after transplantation of pig pancreatic anlagen.

The insufficient supply of tissue, loss posttransplantation, and limited potential for expansion of beta-cells restrict the use of islet allotransplantation for diabetes. A way to overcome the supply and expansion problems is to xenotransplant embryonic tissue. We have shown that whole rat pancreatic anlagen isotransplanted into the omentum of rats, or xenotransplanted into costimulatory blocked mice, undergo growth and differentiate into islets surrounded by stoma without exocrine tissue. Isotransplants normalize glucose tolerance in diabetic hosts. Here, we show that embryonic day 29 porcine pancreas transplanted into the omentum of adult diabetic rats undergoes endocrine tissue differentiation over 20 wk and normalizes body weights and glucose tolerance. Unlike rat-to-rodent transplants, individual alpha- and beta-cells engraft without a stromal component, and no immunosuppression is required for pig-to-rat transplants. Herein is described a novel means to effect the xenotransplantation of individual islet cells across a highly disparate barrier.

Animals↗
PubMed2003

Microvessel formation from mouse aorta is stimulated in vitro by secreted VEGF and extracts from metanephroi.

We have demonstrated that during culture under 5% O(2,) the addition of recombinant human VEGF or FGF2 to mouse embryonic aorta explants (thoracic level to lateral vessels supplying the mesonephros and metanephros) stimulates microvessel formation. Here we show that microvessel formation is also stimulated by addition to explants of supernatants obtained from metanephroi grown in serum-free organ culture or of metanephroi extracts. Supernatants and extracts from metanephroi grown under hypoxic conditions are more stimulatory than supernatants/extracts from metanephroi grown in room air. VEGF and FGF2 can be detected by using immunohistochemistry in developing nephrons in the cultured renal anlagen. Metanephroi supernatants contain more VEGF if renal anlagen are grown under hypoxic conditions than if they are grown in room air. Metanephros supernatant-stimulated microvessel formation is completely inhibited by soluble sFlt-1 fusion protein or anti-VEGF antibodies (alphaVEGF). Extract-stimulated microvessel formation is inhibited by alphaVEGF or anti-FGF2 antibodies, or both. We conclude that metanephroi produce growth factors including VEGF and FGF that enhance microvessel formation from embryonic thoracic aorta in vitro.

Animals↗