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Adult stem cells derived from human goiters form spheres in response to intense growth stimulation and differentiate TSH-dependently into thyroid cells
Title,contents and abbrieviations
Introduction
Materials and methods
Results
Discussion
Summary and reference AcknowledgementsIn recent years, adult stem cells have become the subject of intense study.
The presence of adult stem cells in human thyroid nodule tissues was first
reported in our previous study. However, the isolation of thyroid stem cells
has so far been hampered by the absence of a surface antigen that allows the
separation by FACS. Therefore, this study aimed to analyze (1) under which
conditions quiescent stem cells derived from human nodules can be propagated
to outgrow and (2) if these cells have retained the capacity to differentiate
into thyroid cells. Stem cells from human nodules were isolated as a side
population from a non-side population fraction by FACS. Thyroid SP exhibited a
characteristic morphology of adult stem cells, as compared with non-SP cells,
after cytospin and Giemsa staining. Moreover, because of the poor viability
and growth of SP cells, new isolation and stimulation techniques for stem
cells were employed. Intense growth stimulation of stem cells resulted in
formation of non-adherent, three-dimensional spheres that consisted of highly
proliferating stem and progenitor cells with their characteristic expression
profiles. In response to TSH and serum these sphere-forming cells grew as
monolayer and differentiated into thyrocytes that expressed thyroid specific
genes and showed specific 125iodide uptake. This study demonstrates that human
thyroid nodule tissues contain a population of stem cells with SP phenotype
and the capacity of clonal expansion in response to intense growth
stimulation. These stem cells express typical gene profiles and are
characterized by the ability of self-renewal and differentiation into thyroid
cells. Compared to thyrocytes, stem cells display a much higher proliferation
rate upon acute growth stimulation which suggests a putative role of stem
cells in the chronic growth factor-stimulated nodular transformation of the
thyroid.In den letzten Jahren sind adulte Stammzellen Gegenstand intensiver Forschung.
In den vorausgehenden Arbeiten unserer Arbeitsgruppe konnte zum ersten Mal der
Nachweis von adulten Stammzellen in menschlichen SchilddrĂĽsengeweben gefĂĽhrt
werden. Bislang ist jedoch die Isolation von SchilddrĂĽsenstammzellen aus dem
Schilddrüsengewebe am Fehlen spezifischer Oberflächlichen-Antigenen
gescheitert. Solche Antigenmarker sind fĂĽr die Selektion und Isolierung
intakter Zellen mittels FACS erforderlich. In der vorliegenden Arbeit sollten
daher 1. die Bedingungen analysiert werden, unter denen die aus menschlichen
SchilddrĂĽsenknoten stammende, ruhenden (d.h. nicht proliferierenden)
Stammzellen zum Wachstum gebracht werden können und 2. die Frage geklärt
werden, ob diese Zellen das Potenzial zur Differenzierung in
SchilddrĂĽsenzellen beibehalten haben. Die in dieser Arbeit angewandte
Isolationstechnik von SchilddrĂĽsenstammzellen aus menschlichen
SchilddrĂĽsenknoten mittels FACS. Aufgrund dieser typischen
Genexpressionsprofile konnten eine Seitenpopulation (sogen. side population)
von Stammzellen (SP-Zellen) von den ĂĽbrigen Zellen der SchilddrĂĽse (non-SP-
Zellfraktion) differenziert werden. Morphologisch wiesen die SP-Zellen
lichtmikroskopisch eine charakteristische Stammzellmorphologie. Die Vermehrung
und Differenzierung von isolierten Stammzellen wurde jedoch durch ihren
Ruhezustand (sogen. quiescent state)und ihre verminderte Lebensfähigkeit in
vitro begrenzt. Dieses Problem konnte durch neue Isolation- und
Stimulationsmethoden ĂĽberwunden werden. Nach intensiver Wachstumsstimulation
wuchs eine kleine Zahl von Schilddrüsenstammzellen aus primären Zellkulturen
heran und bildete dreidimensionale kugelförmige Klone. Diese nannten wir
thyro- spheres . Diese thyro-spheres bestanden aus sich stark vermehrenden
Stamm- und Vorläuferzellen mit typischen Genexpressionsprofilen. Nach
Induktion der Differenzierung durch Serum und TSH, wuchsen diese thyro-
spheres -Zellen als Monolayer aus und lieĂźen sich in Thyreozyten mit typischen
mRNA-Expressionsmustern differenzieren. Von besonderer Bedeutung war der
Befund, dass nach Einbetten in Kollagen diese Zellen eine spezifische
125Jodid-Aufnahme aufwiesen. Diese Arbeit zeigt, dass menschliche
Schilddrüsenknotengewebe Stammzellen enthalten, die einen SP-Phänotyp besitzen
und ein Potenzial zur klonalen Expansion nach intensiver Wachstumsstimulation
aufweisen. Diese Stammzellen exprimieren typische Genprofile und besitzen
unter charakteristischen Kulturbedingungen ein Eigenvermehrungs- und Differen-
zierungspotenzial. Im Vergleich zu Thyreozyten, weisen diese Stammzellen nach
akuter Wachstumsstimulation eine erhöhte Proliferationsrate auf. Dies könnte
auf eine mögliche Rolle von Stamm- bzw. Progenitorzellen bei der durch
chronische Wachstumsstimulation induzierten, nodulären Transformation der
SchilddrĂĽse hindeuten
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