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Co-transplantation of Human Pancreatic Islets With Post-migratory Neural Crest Stem Cells Increases beta-Cell Proliferation and Vascular And Neural Regrowth
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Regenerativ neurobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
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2015 (Engelska)Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 100, nr 4, s. E583-E590Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Context: Neural crest stem cells (NCSCs) are capable of substantially improving murine islet function by promoting beta-cell proliferation. Objective: The present study aimed to investigate the potential of NCSCs to stimulate human beta-cell proliferation, and improve neural and vascular engraftment of human islets. Design, Setting, and Subjects: Human pancreatic islets from 18 brain-dead cadaveric donors (age range, 19-78 y) were obtained through the Nordic Network for Clinical Islet Transplantation. beta-cell proliferation and graft function was investigated at our experimental laboratory. Intervention and Main Outcome Measures: Human islets were transplanted, either alone or together with spheres of NCSCs. beta-cell proliferation, as well as islet neuralandvascular densities, were assessed by immunohistochemistry. Graft blood perfusion and oxygen tension were measured using laser-Doppler flowmetry and Clark microelectrodes, respectively. Results: Two days posttransplantation, the number of Ki67-positive beta-cells was doubled in human islets that had been exposed to NCSCs. Similar findings were obtained in vitro, as well as with EdU as proliferation marker. Four weeks posttransplantation, NCSC-exposed human islet grafts had much higher neural and vascular densities. The newly formed blood vessels were also functional, given that these human islets had a substantially higher blood perfusion and oxygen tension when compared with control transplants. Conclusion: We conclude that exposure to NCSCs stimulates human beta-cell proliferation, andthat these cells improve both the neural and vascular engraftment of transplanted human islets. NCSCs are a promising cellular therapy for translation into clinical use.

Ort, förlag, år, upplaga, sidor
2015. Vol. 100, nr 4, s. E583-E590
Nationell ämneskategori
Endokrinologi och diabetes
Identifikatorer
URN: urn:nbn:se:uu:diva-253267DOI: 10.1210/jc.2014-4070ISI: 000353361500009PubMedID: 25668197OAI: oai:DiVA.org:uu-253267DiVA, id: diva2:813912
Tillgänglig från: 2015-05-25 Skapad: 2015-05-25 Senast uppdaterad: 2017-12-04Bibliografiskt granskad
Ingår i avhandling
1. Auxiliary Cells for the Vascularization and Function of Endogenous and Transplanted Islets of Langerhans
Öppna denna publikation i ny flik eller fönster >>Auxiliary Cells for the Vascularization and Function of Endogenous and Transplanted Islets of Langerhans
2017 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Type 1 diabetes develops through the progressive destruction of the insulin-producing beta-cells. Regeneration or replacement of beta-cells is therefore needed to restore normal glucose homeostasis. Presently, normoglycemia can be achieved by the transplantation of whole pancreas or isolated islets of Langerhans. Islet transplantation can be performed through a simple laparoscopic procedure, but the long-term graft survival is low due to poor revascularization and early cell death.

This thesis examined the possibility of using different auxiliary cells (Schwann cells, endothelial progenitor cells, and neural crest stem cells) to improve the engraftment and function of endogenous and transplanted islets.

Co-transplantation of Schwann cells with islets improved islet graft function early after transplantation, and caused an increased islet mass at one month posttransplantation. However, the vascular densities of these grafts were decreased, which also related to an impaired graft function.

Islet grafts containing endothelial progenitor cells had a superior vascular density, with functional chimeric blood vessels and substantially higher blood perfusion and oxygen tension than control transplants.

By culturing and transplanting islets together with neural crest stem cells it was found that islets exposed to these cells had a higher beta-cell proliferation compared with control islets. At one month posttransplantation, the grafts with neural crest stem cells also had a superior vascular- and neural density.

The potential of intracardially injected neural crest stem cells to home to the pancreas and ameliorate hyperglycemia in diabetic mice was investigated. During a three-week period after such cell treatment blood glucose concentrations decreased, but were not fully normalized. Neural crest stem cells were present in more than 10% of the pancreatic islets at two days postinjection, at which time the beta-cell proliferation was markedly increased when compared with islets of saline-treated diabetic animals. Three weeks later, a doubled beta-cell mass was observed in animals receiving neural crest stem cells.

In summary, islets can easily be transplanted together with different auxiliary cells. Some of these cells provide the possibility of improving vascular- and neural engraftment, as well as beta-cell growth and survival. Systemic administration of neural crest stem cells holds the potential of regenerating the endogenous beta-cells.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2017. s. 56
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1348
Nyckelord
Islets of Langerhans, beta cells, diabetes, transplantation, vascularization, Schwann cells, endothelial progenitor cells, neural crest stem cells
Nationell ämneskategori
Medicin och hälsovetenskap
Forskningsämne
Medicinsk vetenskap
Identifikatorer
urn:nbn:se:uu:diva-327314 (URN)978-91-513-0023-8 (ISBN)
Disputation
2017-09-26, C2:301, BMC, Husargatan 3, Uppsala, 10:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2017-09-05 Skapad: 2017-08-09 Senast uppdaterad: 2017-09-08

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Grapensparr, LizaVasylovska, SvitlanaLi, ZhanchunOlerud, JohanJansson, LeifKozlova, ElenaCarlsson, Per-Ola

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Grapensparr, LizaVasylovska, SvitlanaLi, ZhanchunOlerud, JohanJansson, LeifKozlova, ElenaCarlsson, Per-Ola
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Integrativ FysiologiRegenerativ neurobiologiInstitutionen för medicinsk cellbiologiKlinisk immunologiTransplantation och regenerativ medicin
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Journal of Clinical Endocrinology and Metabolism
Endokrinologi och diabetes

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