Endothelial Progenitor Cells Enhance Islet Engraftment, Influence β-Cell Function, and Modulate Islet Connexin 36 Expression

Penko, Daniella; Rojas-Canales, Darling; Mohanasundaram, Daisy; Peiris, Heshan; Sun, Wenxue; Drogemuller, Chris; Keating, Damien J.; Coates, P. Toby; Bonder, Claudine S.; Jessup, Claire F.

doi:10.3727/096368913x673423

Cited by 35 publications

(36 citation statements)

References 43 publications

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“…During enzymatic isolation from the donor pancreas, islets come under a myriad of cellular assaults, including ischemia, physical stress, and loss of contact with key basement membrane proteins and signaling molecules (53), resulting in a substantial loss of viability before transplantation. Clinically, islets are cultured prior to transplantation, and intraislet ECs reduce rapidly in this period (54,55). Therefore, not only do islet transplants face multiple cytotoxic challenges, but they are depleted of the building blocks required for rapid revascularization.…”

Section: Implications Of the B-cell/ec Axis In Pancreatic Islet Transmentioning

confidence: 99%

“…Despite showing no difference in vessel density at 1 month, there was improved glycemic control in cotransplanted animals due to an increase in engrafted b-cell mass, highlighting the impact of hastening early revascularization events. More recently, researchers have used syngeneic models to show that cotransplanted murine EPCs improve the cure rate, function, and vascularization of a marginal transplanted islet mass (81,55). Observations that the EPCs localized within and around the islet mass and that VEGF was produced by these cells, suggest that EPCs may act in a paracrine and autocrine manner to improve islet engraftment.…”

Section: Restoration Of the B-cell/ec Axis With Endothelial Progenitomentioning

confidence: 99%

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The β-Cell/EC Axis: How Do Islet Cells Talk to Each Other?

et al. 2013

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Within the pancreatic islet, the β-cell represents the ultimate biosensor. Its central function is to accurately sense glucose levels in the blood and consequently release appropriate amounts of insulin. As the only cell type capable of insulin production, the β-cell must balance this crucial workload with self-preservation and, when required, regeneration. Evidence suggests that the β-cell has an important ally in intraislet endothelial cells (ECs). As well as providing a conduit for delivery of the primary input stimulus (glucose) and dissemination of its most important effector (insulin), intraislet blood vessels deliver oxygen to these dense clusters of metabolically active cells. Furthermore, it appears that ECs directly impact insulin gene expression and secretion and β-cell survival. This review discusses the molecules and pathways involved in the crosstalk between β-cells and intraislet ECs. The evidence supporting the intraislet EC as an important partner for β-cell function is examined to highlight the relevance of this axis in the context of type 1 and type 2 diabetes. Recent work that has established the potential of ECs or their progenitors to enhance the re-establishment of glycemic control following pancreatic islet transplantation in animal models is discussed.

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Section: Implications Of the B-cell/ec Axis In Pancreatic Islet Transmentioning

confidence: 99%

Section: Restoration Of the B-cell/ec Axis With Endothelial Progenitomentioning

confidence: 99%

The β-Cell/EC Axis: How Do Islet Cells Talk to Each Other?

et al. 2013

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“…The primary source of EPCs from rodents has been from whole or sorted BM and to a lesser extent PB and spleen MNCs [20,44,[53][54][55][56][57][58][59][60]. Similar to the human system, a unique identification signature for murine EPCs still remains elusive, with reported phenotypic overlap with macrophages and dendritic cells combined with inconsistent EPC phenotypes in different rodent strains [20].…”

Section: Rodent Epcsmentioning

confidence: 99%

Regulation of EPCs: The Gateway to Blood Vessel Formation

Parham

Pitson

Bonder

2014

New Journal of Science

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Endothelial progenitor cells (EPCs) are primitive endothelial precursors which are known to functionally contribute to the pathogenesis of disease. To date a number of distinct subtypes of these cells have been described, with differing maturation status, cellular phenotype, and function. Although there is much debate on which subtype constitutes the true EPC population, all subtypes have endothelial characteristics and contribute to neovascularisation. Vasculogenesis, the process by which EPCs contribute to blood vessel formation, can be dysregulated in disease with overabundant vasculogenesis in the context of solid tumours, leading to tumour growth and metastasis, and conversely insufficient vasculogenesis can be present in an ischemic environment. Importantly, it is widely known that transcription factors tightly regulate cellular phenotype and function by controlling the expression of particular target genes and in turn regulating specific signalling pathways. This suggests that transcriptional regulators may be potential therapeutic targets to control EPC function. Herein, we discuss the observed EPC subtypes described in the literature and review recent studies describing the role of a number of transcriptional families in the regulation of EPC phenotype and function in normal and pathological conditions.

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“…Mice were nephrectomized $100 days postgrafting to determine graft dependence of euglycemia. Kidneys containing islet grafts were formalin fixed and embedded for histological analysis (19).…”

Section: Skin and Islet Transplantationmentioning

confidence: 99%

Antigen-Encoding Bone Marrow Terminates Islet-Directed Memory CD8+ T-Cell Responses to Alleviate Islet Transplant Rejection

et al. 2016

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Islet-specific memory T cells arise early in type 1 diabetes (T1D), persist for long periods, perpetuate disease, and are rapidly reactivated by islet transplantation. As memory T cells are poorly controlled by "conventional" therapies, memory T cell-mediated attack is a substantial challenge in islet transplantation, and this will extend to application of personalized approaches using stem cell-derived replacement b-cells. New approaches are required to limit memory autoimmune attack of transplanted islets or replacement b-cells. Here, we show that transfer of bone marrow encoding cognate antigen directed to dendritic cells, under mild, immune-preserving conditions, inactivates established memory CD8 + T-cell populations and generates a long-lived, antigen-specific tolerogenic environment. Consequently, CD8 + memory T cell-mediated targeting of islet-expressed antigens is prevented and islet graft rejection alleviated. The immunological mechanisms of protection are mediated through deletion and induction of unresponsiveness in targeted memory T-cell populations. The data demonstrate that hematopoietic stem cell-mediated gene therapy effectively terminates antigenspecific memory T-cell responses, and this can alleviate destruction of antigen-expressing islets. This addresses a key challenge facing islet transplantation and, importantly, the clinical application of personalized b-cell replacement therapies using patient-derived stem cells.

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Endothelial Progenitor Cells Enhance Islet Engraftment, Influence β-Cell Function, and Modulate Islet Connexin 36 Expression

Cited by 35 publications

References 43 publications

The β-Cell/EC Axis: How Do Islet Cells Talk to Each Other?

The β-Cell/EC Axis: How Do Islet Cells Talk to Each Other?

Regulation of EPCs: The Gateway to Blood Vessel Formation

Antigen-Encoding Bone Marrow Terminates Islet-Directed Memory CD8+ T-Cell Responses to Alleviate Islet Transplant Rejection

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