Stimulated Endocrine Cell Proliferation and Differentiation in Transplanted Human Pancreatic Islets

Tyrberg, Björn; Ustinov, Jarkko; Otonkoski, Timo; Andersson, Arne

doi:10.2337/diabetes.50.2.301

Cited by 71 publications

(45 citation statements)

References 48 publications

(51 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…At post-transplant week 10, BrdU-positive endocrine cells were found in four out of six implants of young donor preparations, while none were detected in the eight implants from older donors. The per-centage of BrdU-positive synaptophysin or insulincontaining cells varied from 0.2 to 1%, which is higher than the BrdU incorporation values (less than 0.2%) in previously reported human islet implants [35,36,37]. These synaptophysin or insulin BrdUpositive cells were encountered in endocrine cell clusters and did not occur as isolated units along ducts.…”

Section: Discussioncontrasting

confidence: 56%

Formation of insulin-positive cells in implants of human pancreatic duct cell preparations from young donors

et al. 2003

View full text Add to dashboard Cite

Aims/hypothesis. Pancreatic ducts are considered as potential sites for neogenesis of beta cells. In vitro studies have reported formation of islets from postnatal human and rodent duct tissue. We examined whether postnatal human duct-cell preparations can generate new beta cells after transplantation. Methods. Pancreatic duct cells were prepared from the non-endocrine fraction of human donor pancreases that were processed for islet-cell isolation. Grafts containing 0.5 million duct cells with 1% contaminating insulin-positive cells were implanted under the kidney capsule of normoglycaemic nude mice. At 0.5 and 10 weeks post-transplantation, implants were examined for their cellular composition and for the volumes of their composing cell populations, i.e. cytokeratin 19-positive duct cells, synaptophysin-, insulin-and glucagon-positive endocrine cells. Results. Between week 0.5 and 10, duct-cell volume decreased by at least 90% whereas the change in insulin-positive cell volume depended on donor age. Implants from donors over10 years had a threefold decrease in their insulin-positive cell volume, while those from donors under 10 years had a 2.5-fold increase. After 10 weeks, the implants from the younger donors consisted of 19% insulin-positive cells occurring as single units or small cell clusters. Three percent of these insulin-positive cells also expressed the ductal marker CK 19 and were consistently found in conjunction with ductal epithelia; up to 1% was positive for the proliferation marker BrdU and located in small endocrine cell clusters. Conclusions/interpretation. These data indicate that duct cell preparations from donors under 10 years can generate insulin-positive cells. This process might involve differentiation of CK 19-positive-insulin cells that are formed at the duct epithelia as well as proliferation of insulin-positive cells within endocrine cell aggregates. [Diabetologia (2003) 46:830-838]

show abstract

Section: Discussioncontrasting

confidence: 56%

Formation of insulin-positive cells in implants of human pancreatic duct cell preparations from young donors

et al. 2003

View full text Add to dashboard Cite

show abstract

“…A normoglycaemic environment, in contrast to hyperglycaemia, provides better islet transplantation results [14,17,18] for uncertain reasons that may include enhanced beta cell growth of the grafts [19], and/or avoidance of hyperglycaemia-induced increased oxygen demand with resulting hypoxia, a pro-apoptotic state of beta cells, and less-efficient vascularisation [20,21], although it seems that in the long term, vascular density is unchanged by hyperglycaemia [22]. It cannot be ruled out that nephrectomy leads to release of compensatory growth factors in the contralateral kidney where the 75-islet graft is situated, thus stimulating islet growth [23]; even so, a remarkably low number of islets was required to maintain normoglycaemia. In the mice transplanted with 75 fresh islets or 150 cultured islets, the treatment of the mice with exendin-4 did not improve the outcome with regard to the mean time to cure or blood glucose levels.…”

Section: Discussionmentioning

confidence: 99%

Islet transplantation outcomes in mice are better with fresh islets and exendin-4 treatment

King

Lock

et al. 2005

Diabetologia

View full text Add to dashboard Cite

Aims/hypothesis: Although islet transplantation in diabetes holds great promise, two or three donor pancreases are usually required to achieve normoglycaemia in human or rodent recipients. We investigated whether there were differences between fresh and cultured islets in terms of transplantation outcome. We also investigated the effects of normoglycaemia during engraftment and the effects of exendin-4, a glucagon-like peptide-1 receptor agonist, on islet transplantation. Materials and methods: Seventy-five fresh islets were transplanted to the right kidney of diabetic mice and 425 fresh islets were transplanted to the left kidney. The mice were treated with exendin-4 or vehicle for 14 days, after which the large graft was removed by left nephrectomy. In a separate set of experiments, islets cultured in the presence or absence of exendin-4 for 72 h, or fresh islets, were transplanted to diabetic mice. In both sets of experiments, blood glucose levels were monitored. Results: Compared with cultured islets, fresh islets were more effective at reversing hyperglycaemia in mice. The treatment of the recipient mice with exendin-4 did not have beneficial effects on glucose homeostasis. However, when islets are cultured, exendin-4 treatment increases the rate of reversal of hyperglycaemia, but not to the degree of fresh islets. Conclusions/ interpretation: Fresh islets are more effective than cultured islets at reversing hyperglycaemia. Exendin-4 has beneficial effects on islet transplantation.

show abstract

“…Yet, β-cell proliferation in adult humans has been reported as extremely low, and greatly enlarged islets are rarely found. In autopsied human pancreata, β-cell replication (Ki67 + β-cells) drops to less than 0.2% already by 5 years of age [58], in another study to about 0.5% in adolescents [60], and can be almost negligible in adults [60,62,67,68]. However, this low level of detection may result from the tissue being only retrieved after death.…”

Section: Evidence Of Compensatory Expansion In the Adult Human Pancreasmentioning

confidence: 92%

Islet Neogenesis: A Possible Pathway for Beta-Cell Replenishment

Bonner-Weir

Guo

Li³

et al. 2012

Rev Diabet Stud

View full text Add to dashboard Cite

■ AbstractDiabetes, particularly type 1 diabetes, results from the lack of pancreatic β-cells. β-cell replenishment can functionally reverse diabetes, but two critical challenges face the field: 1. protection of the new β-cells from autoimmunity and allorejection, and 2. development of β-cells that are readily available and reliably functional. This chapter will examine the potential of endogenous replenishment of pancreatic β-cells as a possible therapeutic tool if autoimmunity could be blunted. Two pathways for endogenous replenishment exist in the pancreas: replication and neogenesis, defined as the formation of new islet cells from pancreatic progenitor/stem cells. These pathways of β-cell expansion are not mutually exclusive and both occur in embryonic development, in postnatal growth, and in response to some injuries. Since the β-cell population is dramatically reduced in the pancreas of type 1 diabetes patients, with only a small fraction of the β-cells surviving years after onset, replication of preexisting β-cells would not be a reasonable start for replenishment. However, induction of neogenesis could provide a starting population that could be further expanded by replication. It is widely accepted that neogenesis occurs in the initial embryonic formation of the endocrine pancreas, but its occurrence anytime after birth has become controversial because of discordant data from lineage tracing experiments. However, the concept was built upon many observations from different models and species over many years. Herein, we discuss the role of neogenesis in normal growth and regeneration, as learned from rodent models, followed by an analysis of what has been found in humans.

show abstract

Stimulated Endocrine Cell Proliferation and Differentiation in Transplanted Human Pancreatic Islets

Cited by 71 publications

References 48 publications

Formation of insulin-positive cells in implants of human pancreatic duct cell preparations from young donors

Formation of insulin-positive cells in implants of human pancreatic duct cell preparations from young donors

Islet transplantation outcomes in mice are better with fresh islets and exendin-4 treatment

Islet Neogenesis: A Possible Pathway for Beta-Cell Replenishment

Contact Info

Product

Resources

About