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Adult Stem Cell Plasticity, Hype or Hope?

Taneera, Jalal LU (2007)
Abstract (Swedish)
Popular Abstract in Swedish

Stamceller i benmärgen reglerar balansen mellan att upprätthålla populationen av stamceller (självförnyelse) samt att producera mogna blodceller.



Det finns flera studier om förmågan hos benmärgsderiverade stamceller att ge upphov till andra celltyper än blodceller, såsom hjärnceller, leverceller, muskel, hjärta, blodkärl, lungceller, tarm, hud och insulin-producerande beta-celler. Denna förmåga kallas stamcellsplasticitet eller transdifferentiering och utmanar dogman att adulta stamceller enbart kan ge upphov till celler inom samma groddblad.



Det övergripande målet för denna avhandling har varit att utvärdera och undersöka plasticiteten hos... (More)
Popular Abstract in Swedish

Stamceller i benmärgen reglerar balansen mellan att upprätthålla populationen av stamceller (självförnyelse) samt att producera mogna blodceller.



Det finns flera studier om förmågan hos benmärgsderiverade stamceller att ge upphov till andra celltyper än blodceller, såsom hjärnceller, leverceller, muskel, hjärta, blodkärl, lungceller, tarm, hud och insulin-producerande beta-celler. Denna förmåga kallas stamcellsplasticitet eller transdifferentiering och utmanar dogman att adulta stamceller enbart kan ge upphov till celler inom samma groddblad.



Det övergripande målet för denna avhandling har varit att utvärdera och undersöka plasticiteten hos benmärgsstamceller, närmare bestämt om de kan ge upphov till insulinproducerande celler, endotel (inre väggen av blodkärl) och hjärtmuskelceller under normala tillstånd samt efter specifik vävnadsskada.



Vi visade att benmärgsderiverade stamceller efter benmärgstransplantation kan migrera till pankreas i normala och diabetiska möss. Det stora flertalet av dessa celler var blodceller. Inga insulinproducerande celler deriverade från benmärg hittades. I en andra studie undersökte vi om benmärgstransplantation bidrar till nybildning av kärl i pankreas samt om endotelceller från dessa kärl kan stimulera en ökning av antalet beta-celler i normala respektive diabetiska möss. En liten andel av de benmärgsderiverade cellerna i pankreas uttryckte endotelmarkören vWF (von Willebrandfaktor). Karakterisering av de prolifererande celler med BrdU visade att 1,3% av BrdU-uttryckande celler var beta-celler i hyperglykemiska möss. Dessutom uttryckte 9% av de BrdU-positiva cellerna endotelmarkören vWF. I en tredje studie visades att celler från benmärgen kan migrera till skadad hjärtvävnad men uttryckte inte några hjärtmuskelmarkörer. En intressant observation var att en låg frekvens av benmärgsderiverade hjärtmuskelceller observerades utanför skadeområdet i hjärtat. Ytterligare analys visade att dessa celler hade bildats genom fusion mellan hjärtmuskelceller och celler från benmärgen. (Less)
Abstract
Several studies have reported that bone marrow (BM)-derived stem cells have the capacity to give rise to cells of different type of tissue; an ability termed stem cell plasticity or transdifferentiation. Controversies exist as to how frequent this phenomenon is, or if it may be explained by alternative mechanisms. Here we have used different mouse models to study the potential plasticity of BM-derived stem cells.



In the first two studies aiming at defining how BM transplantation may contribute to generation of pancreatic beta-cells, we first demonstrated that BM cells readily engraft recipient pancreas in normal and diabetic mice. Engrafted cells expressed the hematopoietic marker CD45 (CD45+), but no beta-cell markers,... (More)
Several studies have reported that bone marrow (BM)-derived stem cells have the capacity to give rise to cells of different type of tissue; an ability termed stem cell plasticity or transdifferentiation. Controversies exist as to how frequent this phenomenon is, or if it may be explained by alternative mechanisms. Here we have used different mouse models to study the potential plasticity of BM-derived stem cells.



In the first two studies aiming at defining how BM transplantation may contribute to generation of pancreatic beta-cells, we first demonstrated that BM cells readily engraft recipient pancreas in normal and diabetic mice. Engrafted cells expressed the hematopoietic marker CD45 (CD45+), but no beta-cell markers, e.g. insulin or transcription factors pdx 1 or Nkx6.1. However, a subset of engrafted BM cells also expressed endothelial markers von Willebrand factor (vWF) and CD31/PECAM. In mice treated with different dosages of the beta-cell toxin streptozotocin (STZ) to induce diabetes, the fraction of CD45+vWF+ cells increased with the STZ dose. This coincided with increased proliferation BrdU+ cells in both vWF+ and insulin+ cells.



In a third study evaluating BM plasticity in mouse models of myocardial infarction, we showed that BM-derived stem cells efficiently engraft the infarcted myocardium, without any signs of transdifferentiation. A very small population (0.75%) of the BM-derived cells exhibiting a cardiomyocyte phenotype was observed outside the infarcted myocardium. Further analysis showed that these cells were derived through cell fusion.



In summary, this thesis challenges the view that BM-derived stem directly transdifferentiate into cardiomyocytes or pancreatic beta-cells. However, BM cells may stimulate pancreatic ?-cell proliferation indirectly, possibly by adopting an endothelial phenotype. These results underline the importance of thorough studies at the cellular level before initiation of clinical BM transplantation trials. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Ass. Prof. Heller, Scott, Hegedorn Research Institute, Denmark
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Medicine (human and vertebrates), 'pancreatic beta cell', 'stem cell', 'plasticity', Medicin (människa och djur)
pages
64 pages
publisher
Clinical Research Center Islet pathophysiology UMAS, Malmö Lund University
defense location
Clinical Research Center, CRC UMAS, Malmö Ingång 72, Aula
defense date
2007-03-30 13:15
ISSN
1652-8220
ISBN
978-91-85559-32-9
language
English
LU publication?
yes
id
054f6458-10c4-4303-85e5-a8bfd0b34f92 (old id 548260)
date added to LUP
2007-09-12 09:57:46
date last changed
2016-09-19 08:44:58
@phdthesis{054f6458-10c4-4303-85e5-a8bfd0b34f92,
  abstract     = {Several studies have reported that bone marrow (BM)-derived stem cells have the capacity to give rise to cells of different type of tissue; an ability termed stem cell plasticity or transdifferentiation. Controversies exist as to how frequent this phenomenon is, or if it may be explained by alternative mechanisms. Here we have used different mouse models to study the potential plasticity of BM-derived stem cells.<br/><br>
<br/><br>
In the first two studies aiming at defining how BM transplantation may contribute to generation of pancreatic beta-cells, we first demonstrated that BM cells readily engraft recipient pancreas in normal and diabetic mice. Engrafted cells expressed the hematopoietic marker CD45 (CD45+), but no beta-cell markers, e.g. insulin or transcription factors pdx 1 or Nkx6.1. However, a subset of engrafted BM cells also expressed endothelial markers von Willebrand factor (vWF) and CD31/PECAM. In mice treated with different dosages of the beta-cell toxin streptozotocin (STZ) to induce diabetes, the fraction of CD45+vWF+ cells increased with the STZ dose. This coincided with increased proliferation BrdU+ cells in both vWF+ and insulin+ cells.<br/><br>
<br/><br>
In a third study evaluating BM plasticity in mouse models of myocardial infarction, we showed that BM-derived stem cells efficiently engraft the infarcted myocardium, without any signs of transdifferentiation. A very small population (0.75%) of the BM-derived cells exhibiting a cardiomyocyte phenotype was observed outside the infarcted myocardium. Further analysis showed that these cells were derived through cell fusion.<br/><br>
<br/><br>
In summary, this thesis challenges the view that BM-derived stem directly transdifferentiate into cardiomyocytes or pancreatic beta-cells. However, BM cells may stimulate pancreatic ?-cell proliferation indirectly, possibly by adopting an endothelial phenotype. These results underline the importance of thorough studies at the cellular level before initiation of clinical BM transplantation trials.},
  author       = {Taneera, Jalal},
  isbn         = {978-91-85559-32-9},
  issn         = {1652-8220},
  keyword      = {Medicine (human and vertebrates),'pancreatic beta cell','stem cell','plasticity',Medicin (människa och djur)},
  language     = {eng},
  pages        = {64},
  publisher    = {Clinical Research Center Islet pathophysiology UMAS, Malmö Lund University},
  school       = {Lund University},
  title        = {Adult Stem Cell Plasticity, Hype or Hope?},
  year         = {2007},
}