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In vivo and in vitro approaches to induce beta cells from stem and progenitor cells
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). (Helena Edlund)
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diabetes or diabetes mellitus which is the correct medical term is a medical condition were the affected person lack the ability to regulate his or her blood glucose levels. This inability is directly due to the fact that the insulin producing cells, residing in the pancreas, can’t meet the body’s demand for insulin. It is estimated that close to 200 million people are suffering from diabetes today and this number is predicted to double within 20 years. Of the approximately 200 million people suffering from diabetes today approximately 20 million are in dependent on daily injections of insulin. Being dependent on exogenous insulin is not only an inconvenience it also increase the risk for several medical complications such as stroke, heart disorders, kidney failure, retinopathy, atherosclerosis and impaired wound healing. The major risk factor for all these complications is long periods of high blood sugar levels that is damaging to thin blood vessels and nerves.  Even in the best of situations the blood sugar levels of a diabetic with need for daily insulin injections can never be as well controlled as in a healthy individual.

Increased understanding in the developmental processes behind the formation of the pancreas, and more specifically the insulin producing β-cells could result in new treatments for diabetics. By imitating the in vivo conditions generating pancreatic development scientist are now able to induce embryonic stem cells to differentiate into pancreatic progenitors as well as insulin producing β-cells in vitro. These in vitro generated pancreatic cells might in the future serve as a donor source for transplantations, thereby restoring the insulin producing capability of diabetic patients. An alternative approach to restore insulin production in diabetics is to influence cells in the pancreas to generate more insulin producing cells. To successfully achieve this, what cell types have the capacity to generate β-cells needs to be appreciated.

In this thesis papers concerning in vitro differentiating of embryonic stem cells towards a pancreatic fate as well as in vivo studies in basic pancreas development are presented and discussed.

Place, publisher, year, edition, pages
2009. , 92 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1287
Keyword [en]
pancreas, stem cell, progenitor, beta cell, in vitro
National Category
Medical Genetics
Research subject
Molecular Medicine
Identifiers
URN: urn:nbn:se:umu:diva-25813ISBN: 978-91-7268-846-3 OAI: oai:DiVA.org:umu-25813DiVA: diva2:233964
Distributor:
Umeå centrum för molekylär medicin (UCMM), 90185, Umeå
Public defence
2009-09-25, Major Groove, Byggnad 6L, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2009-09-09 Created: 2009-09-03 Last updated: 2010-01-18Bibliographically approved
List of papers
1. Nestin is expressed in mesenchymal and not epithelial cells of the developing mouse pancreas
Open this publication in new window or tab >>Nestin is expressed in mesenchymal and not epithelial cells of the developing mouse pancreas
2002 (English)In: Mechanisms of Development, ISSN 0925-4773, E-ISSN 1872-6356, Vol. 113, no 2, 189-192 p.Article in journal (Refereed) Published
Abstract [en]

Stem cell research and the prospect of stem cell based therapies depend critically on the identification of specific markers that can be used for the identification and selection of stem and progenitor cells. Nestin is expressed in neuronal progenitor cells and has also been suggested to mark multipotent pancreatic stem cells. We show here that, throughout pancreatic development, markers of pancreatic progenitor cells and differentiated pancreatic cells are expressed in E-cadherin-positive epithelial cells that do not express nestin. The data presented demonstrate that nestin is expressed in mesenchymal and not epithelial cells of the developing mouse pancreas.

Place, publisher, year, edition, pages
Ireland: Elsevier Science, 2002
Keyword
neuronal progenitors; nestin; pancreatic stem cells; embryonic stem cells; embryonic pancreas; epithelium; mesenchyme; insulin; E-cadherin; IPF1/PDX1; ngn3; Isl1; p48
National Category
Developmental Biology
Research subject
Developmental Neurosciences
Identifiers
urn:nbn:se:umu:diva-25796 (URN)
Projects
In vivo and in vitro approaches to induce beta cells from stem and progenitor cells
Available from: 2009-09-03 Created: 2009-09-03 Last updated: 2017-12-13Bibliographically approved
2. Retinoic acid promotes the generation of pancreatic endocrine progenitor cells and their further differentiation into beta-cells
Open this publication in new window or tab >>Retinoic acid promotes the generation of pancreatic endocrine progenitor cells and their further differentiation into beta-cells
Show others...
2008 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 3, no 7, e2841- p.Article in journal (Refereed) Published
Abstract [en]

The identification of secreted factors that can selectively stimulate the generation of insulin producing beta-cells from stem and/or progenitor cells represent a significant step in the development of stem cell-based beta-cell replacement therapy. By elucidating the molecular mechanisms that regulate the generation of beta-cells during normal pancreatic development such putative factors may be identified. In the mouse, beta-cells increase markedly in numbers from embryonic day (e) 14.5 and onwards, but the extra-cellular signal(s) that promotes the selective generation of beta-cells at these stages remains to be identified. Here we show that the retinoic acid (RA) synthesizing enzyme Raldh1 is expressed in developing mouse and human pancreas at stages when beta-cells are generated. We also provide evidence that RA induces the generation of Ngn3(+) endocrine progenitor cells and stimulates their further differentiation into beta-cells by activating a program of cell differentiation that recapitulates the normal temporal program of beta-cell differentiation.

Identifiers
urn:nbn:se:umu:diva-23322 (URN)10.1371/journal.pone.0002841 (DOI)18665267 (PubMedID)
Available from: 2009-06-10 Created: 2009-06-10 Last updated: 2010-04-27Bibliographically approved
3. Increased beta cell mass in mice where FGFR1c is expressed in alpha cells
Open this publication in new window or tab >>Increased beta cell mass in mice where FGFR1c is expressed in alpha cells
(English)Manuscript (preprint) (Other academic)
Abstract [en]

FGFR1 is selectively expressed in adult b- but not a-cells and signalling via FGFR1 is crucial for adult b-cell function. When signalling via the FGFR1c pathway is perturbed in b-cells of genetically modified “FRID1” mice, they develop late-onset diabetes and, remarkably, exhibit the three major b-cell defects observed in human type 2 diabetics; i) Impaired glucose sensing due to perturbed b-cell expression of Glut2; ii) increased proinsulin content in b-cells due to drastically reduced production of PC1/3; the enzyme essential for the generation of mature, biologically active insulin from its precursor form, proinsulin;  iii) a reduced number of b-cells, as compared with matched controls, due to reduced ability of b-cells to divide after birth. Furthermore, the transcription factor IPF1/PDX1, which controls several key functional properties of b-cells and is linked to diabetes in man, is required to maintain FGF-signalling in b-cells. Together these results point to a crucial role for FGFR1-signalling in controlling the generation of normal numbers of b-cells and glucose homeostasis. To further investigate the mechanism by which FGFR1 signalling influences key b-cell properties as well as b-mass we mis-expressed of FGFR1c in a-cells using the glucagon promoter.

Keyword
diabetes pancreas fgf
National Category
Developmental Biology
Research subject
Developmental Neurosciences
Identifiers
urn:nbn:se:umu:diva-25794 (URN)
Projects
In vivo and in vitro approaches to induce beta cells from stem and progenitor cells
Available from: 2009-09-03 Created: 2009-09-03 Last updated: 2010-01-14Bibliographically approved

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