uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
Grapensparr, Liza
Publications (10 of 14) Show all publications
Grapensparr, L., Christoffersson, G. & Carlsson, P.-O. (2018). Bioengineering with Endothelial Progenitor Cells Improves the Vascular Engraftment of Transplanted Human Islets. Cell Transplantation, 27(6), 948-956
Open this publication in new window or tab >>Bioengineering with Endothelial Progenitor Cells Improves the Vascular Engraftment of Transplanted Human Islets
2018 (English)In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 27, no 6, p. 948-956Article in journal (Refereed) Published
Abstract [en]

Pancreatic islets isolated for transplantation are disconnected from their vascular supply and need to establish a new functional network posttransplantation. Due to poor revascularization, prevailing hypoxia with correlating increased apoptosis rates in experimental studies can be observed for months posttransplantation. Endothelial progenitor cells (EPCs) are bone marrow-derived cells that promote neovascularization. The present study tested the hypothesis that EPCs, isolated from human umbilical cord blood, could be coated to human islet surfaces and be used to promote islet vascular engraftment. Control or EPC bioengineered human islets were transplanted into the renal subcapsular space of nonobese diabetic/severe combined immunodeficiency mice. Four weeks posttransplantation, graft blood perfusion and oxygen tension were measured using laser Doppler flowmetry and Clark microelectrodes, respectively. Vessel functionality was also assessed by in vivo confocal imaging. The vascular density and the respective contribution of human and recipient endothelium were assessed immunohistochemically by staining for human and mouse CD31. Islet grafts with EPCs had substantially higher blood perfusion and oxygen tension than control transplants. Furthermore, analysis of the vascular network of the grafts revealed that grafts containing EPC bioengineered islets had a superior vascular density compared with control grafts, with functional chimeric blood vessels. We conclude that a simple procedure of surface coating with EPCs provides a possibility to improve the vascular engraftment of transplanted human islets. Established protocols are also easily applicable for intraportal islet transplantation in order to obtain a novel directed cellular therapy at the site of implantation in the liver.

Keywords
endothelial progenitor cells, islet revascularization, neovascularization, islet engraftment
National Category
Surgery Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-361553 (URN)10.1177/0963689718759474 (DOI)000438945100009 ()29862837 (PubMedID)
Funder
Swedish Research CouncilSwedish Child Diabetes FoundationSwedish Diabetes AssociationEXODIAB - Excellence of Diabetes Research in SwedenTorsten Söderbergs stiftelseNovo NordiskStiftelsen Olle Engkvist ByggmästareAFA Insurance
Available from: 2018-10-08 Created: 2018-10-08 Last updated: 2018-10-08Bibliographically approved
Grapensparr, L. (2017). Auxiliary Cells for the Vascularization and Function of Endogenous and Transplanted Islets of Langerhans. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Auxiliary Cells for the Vascularization and Function of Endogenous and Transplanted Islets of Langerhans
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. p. 56
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1348
Keywords
Islets of Langerhans, beta cells, diabetes, transplantation, vascularization, Schwann cells, endothelial progenitor cells, neural crest stem cells
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-327314 (URN)978-91-513-0023-8 (ISBN)
Public defence
2017-09-26, C2:301, BMC, Husargatan 3, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2017-09-05 Created: 2017-08-09 Last updated: 2017-09-08
Liljebäck, H., Grapensparr, L., Olerud, J. & Carlsson, P.-O. (2016). Extensive Loss of Islet Mass Beyond the First Day After Intraportal Human Islet Transplantation in a Mouse Model. Cell Transplantation, 25(3), 481-489
Open this publication in new window or tab >>Extensive Loss of Islet Mass Beyond the First Day After Intraportal Human Islet Transplantation in a Mouse Model
2016 (English)In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 25, no 3, p. 481-489Article in journal (Refereed) Published
Abstract [en]

Clinical islet transplantation is characterized by a progressive deterioration of islet graft function, which renders many patients once again dependent on exogenous insulin administration within a couple of years. In this study, we aimed to investigate possible engraftment factors limiting the survival and viability of experimentally transplanted human islets beyond the first day after their transplantation to the liver. Human islets were transplanted into the liver of nude mice and characterized 1 or 30 days after transplantation by immunohistochemistry. The factors assessed were endocrine mass, cellular death, hypoxia, vascular density and amyloid formation in the transplanted islets. One day posttransplantation, necrotic cells, as well as apoptotic cells, were commonly observed. In contrast to necrotic death, apoptosis rates remained high 1 month posttransplantation, and the total islet mass was reduced by more than 50% between 1 and 30 days posttransplantation. Islet mass at 30 days posttransplantation correlated negatively to apoptotic death. Vascular density within the transplanted islets remained less than 30% of that in native human islets up to 30 days posttransplantation and was associated with prevailing hypoxia. Amyloid formation was rarely observed in the 1-day-old transplants, but was commonly observed in the 30-day-old islet transplants. We conclude that substantial islet cell death occurs beyond the immediate posttransplantation phase, particularly through apoptotic events. Concomitant low vascularization with prevailing hypoxia and progressive amyloid development was observed in the human islet grafts. Strategies to improve engraftment at the intraportal site or change of implantation site in the clinical setting are needed.

Keywords
Islet transplantation, Diabetes, Amyloid, Engraftment
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-294600 (URN)10.3727/096368915X688902 (DOI)000372669200005 ()26264975 (PubMedID)
Funder
Swedish Research CouncilSwedish Diabetes AssociationSwedish Child Diabetes FoundationNovo Nordisk
Available from: 2016-05-26 Created: 2016-05-25 Last updated: 2017-11-30Bibliographically approved
Jansson, L., Barbu, A., Bodin, B., Drott, C. J., Espes, D., Gao, X., . . . Carlsson, P.-O. (2016). Pancreatic islet blood flow and its measurement. Upsala Journal of Medical Sciences, 121(2), 81-95
Open this publication in new window or tab >>Pancreatic islet blood flow and its measurement
Show others...
2016 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 121, no 2, p. 81-95Article, review/survey (Refereed) Published
Abstract [en]

Pancreatic islets are richly vascularized, and islet blood vessels are uniquely adapted to maintain and support the internal milieu of the islets favoring normal endocrine function. Islet blood flow is normally very high compared with that to the exocrine pancreas and is autonomously regulated through complex interactions between the nervous system, metabolites from insulin secreting beta-cells, endothelium derived mediators, and hormones. The islet blood flow is normally coupled to the needs for insulin release and is usually disturbed during glucose intolerance and overt diabetes. The present review provides a brief background on islet vascular function and especially focuses on available techniques to measure islet blood perfusion. The gold standard for islet blood flow measurements in experimental animals is the microsphere technique, and its advantages and disadvantages will be discussed. In humans there are still no methods to measure islet blood flow selectively, but new developments in radiological techniques hold great hopes for the future.

Keywords
Blood flow measurements, islet blood flow, microspheres, pancreatic islets
National Category
General Practice
Identifiers
urn:nbn:se:uu:diva-299775 (URN)10.3109/03009734.2016.1164769 (DOI)000376695600004 ()27124642 (PubMedID)
Funder
Swedish Research CouncilSwedish Diabetes AssociationSwedish Childhood Cancer FoundationNovo Nordisk
Available from: 2016-07-27 Created: 2016-07-27 Last updated: 2018-01-10Bibliographically approved
Grapensparr, L., Vasylovska, S., Li, Z., Olerud, J., Jansson, L., Kozlova, E. & Carlsson, P.-O. (2015). Co-transplantation of Human Pancreatic Islets With Post-migratory Neural Crest Stem Cells Increases beta-Cell Proliferation and Vascular And Neural Regrowth. Journal of Clinical Endocrinology and Metabolism, 100(4), E583-E590
Open this publication in new window or tab >>Co-transplantation of Human Pancreatic Islets With Post-migratory Neural Crest Stem Cells Increases beta-Cell Proliferation and Vascular And Neural Regrowth
Show others...
2015 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 100, no 4, p. E583-E590Article in journal (Refereed) 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.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-253267 (URN)10.1210/jc.2014-4070 (DOI)000353361500009 ()25668197 (PubMedID)
Available from: 2015-05-25 Created: 2015-05-25 Last updated: 2017-12-04Bibliographically approved
Grapensparr, L. & Carlsson, P.-O. (2015). Intracardially injected neural crest stem cells home to the pancreas and delays disease progression in an animal model for type 1 diabetes. Paper presented at IPITA/IXA/CTS Joint Congress, NOV 15-19, 2015, Melbourne, AUSTRALIA. Xenotransplantation, 22, S198-S199
Open this publication in new window or tab >>Intracardially injected neural crest stem cells home to the pancreas and delays disease progression in an animal model for type 1 diabetes
2015 (English)In: Xenotransplantation, ISSN 0908-665X, E-ISSN 1399-3089, Vol. 22, p. S198-S199Article in journal, Meeting abstract (Other academic) Published
National Category
Other Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-276045 (URN)000364594100487 ()
Conference
IPITA/IXA/CTS Joint Congress, NOV 15-19, 2015, Melbourne, AUSTRALIA
Available from: 2016-02-09 Created: 2016-02-09 Last updated: 2017-11-30Bibliographically approved
Grapensparr, L. & Carlsson, P.-O. (2015). Intracardially Injected Neural Crest Stem Cells Home To The Pancreas And Delays Disease Progression In An Animal Model For Type 1 Diabetes. Paper presented at Joint Congress of the International-Pancreas-and-Islet-Transplantation-Association, International-Xenotransplantation-Association and Cell-Transplant-Society, NOV 15-19, 2015, Melbourne, AUSTRALIA. Transplantation, 99(11), S331-S331
Open this publication in new window or tab >>Intracardially Injected Neural Crest Stem Cells Home To The Pancreas And Delays Disease Progression In An Animal Model For Type 1 Diabetes
2015 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 99, no 11, p. S331-S331Article in journal, Meeting abstract (Other academic) Published
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-281552 (URN)000368625700487 ()
Conference
Joint Congress of the International-Pancreas-and-Islet-Transplantation-Association, International-Xenotransplantation-Association and Cell-Transplant-Society, NOV 15-19, 2015, Melbourne, AUSTRALIA
Available from: 2016-04-05 Created: 2016-03-24 Last updated: 2018-01-10Bibliographically approved
Ullsten, S., Grapensparr, L., Sandberg, M. & Carlsson, P.-O. (2015). Schwann cells regulate angiogenesis and blood vessel structure in native and transplanted pancreatic. Paper presented at IPITA/IXA/CTS Joint Congress, NOV 15-19, 2015, Melbourne, AUSTRALIA. Xenotransplantation, 22, S46-S46
Open this publication in new window or tab >>Schwann cells regulate angiogenesis and blood vessel structure in native and transplanted pancreatic
2015 (English)In: Xenotransplantation, ISSN 0908-665X, E-ISSN 1399-3089, Vol. 22, p. S46-S46Article in journal, Meeting abstract (Other academic) Published
National Category
Other Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-276047 (URN)000364594100109 ()
Conference
IPITA/IXA/CTS Joint Congress, NOV 15-19, 2015, Melbourne, AUSTRALIA
Available from: 2016-02-09 Created: 2016-02-09 Last updated: 2017-11-30Bibliographically approved
Ullsten, S., Grapensparr, L., Sandberg, M. & Carlsson, P.-O. (2015). Schwann Cells Regulate Angiogenesis And Blood Vessel Structure In Native And Transplanted Pancreatic Islets. Paper presented at Joint Congress of the International-Pancreas-and-Islet-Transplantation-Association, International-Xenotransplantation-Association and Cell-Transplant-Society, NOV 15-19, 2015, Melbourne, AUSTRALIA. Transplantation, 99(11), S75-S75
Open this publication in new window or tab >>Schwann Cells Regulate Angiogenesis And Blood Vessel Structure In Native And Transplanted Pancreatic Islets
2015 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 99, no 11, p. S75-S75Article in journal, Meeting abstract (Other academic) Published
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-281554 (URN)000368625700106 ()
Conference
Joint Congress of the International-Pancreas-and-Islet-Transplantation-Association, International-Xenotransplantation-Association and Cell-Transplant-Society, NOV 15-19, 2015, Melbourne, AUSTRALIA
Available from: 2016-04-05 Created: 2016-03-24 Last updated: 2018-01-10Bibliographically approved
Grapensparr, L., Vasylovska, S., Olerud, J., Korsgren, O., Kozlova, E., Jansson, L. & Carlsson, P.-O. (2013). Neural Crest Stem Cells Induce Beta-cell Proliferation in Cultured and Transplanted Human Pancreatic Islets. Paper presented at 14th World Congress of the International-Pancreas-and-Islet-Transplant-Association (IPITA), SEP 24-27, 2013, Monterey, CA. Transplantation, 96(6), S149-S149
Open this publication in new window or tab >>Neural Crest Stem Cells Induce Beta-cell Proliferation in Cultured and Transplanted Human Pancreatic Islets
Show others...
2013 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 96, no 6, p. S149-S149Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-220750 (URN)000330443500270 ()
Conference
14th World Congress of the International-Pancreas-and-Islet-Transplant-Association (IPITA), SEP 24-27, 2013, Monterey, CA
Available from: 2014-03-24 Created: 2014-03-20 Last updated: 2017-12-05Bibliographically approved
Organisations

Search in DiVA

Show all publications