Evidence of in situ proliferation of adult adipose tissue-derived progenitor cells: influence of fat mass microenvironment and growth.
BACKGROUND
Adipocyte formation in human adult adipose tissue (hAT) originates from resident progenitor cell differentiation in the stroma vascular fraction of the AT. The processes involved in the self-renewal of this cell population remain to be defined.


OBJECTIVE
The objective was to study in situ and in vitro hAT progenitor cell (defined as CD34(+)/CD31(-) cells) proliferation.


METHODS
In situ progenitor cell proliferation was assessed by immunohistochemistry and flow cytometry analyses on hAT from lean to obese subjects using the proliferation marker Ki-67. The effects of adipokines, hypoxia, and conditioned media (CM) from adipocytes, capillary endothelial cells, and macrophages isolated by an immunoselection approach were studied on hAT progenitor cell growth. Cell death in hAT was assessed by the terminal deoxynucleotidyl transferase-mediated dUTP-fluorescein end labeling method.


RESULTS
Ki-67-positive staining was observed in AT progenitor cells. Fat mass enlargement in obese patients was associated with an increased Ki-67(+) progenitor cell population together with a new fraction of small adipocytes and increased cell death. HIF-1alpha mRNA expression in freshly harvested progenitor cells was positively correlated with body mass index. Adipocyte- and capillary endothelial cell-CM, hypoxia, leptin, IL-6, lysophosphatidic acid, and vascular endothelial growth factor, all increased hAT progenitor cell proliferation in vitro. Macrophage-CM had an antiproliferative effect that was suppressed by an antioxidant.


CONCLUSIONS
The fraction of proliferative progenitor cells in adult hAT is modulated by the degree of adiposity. Changes in the progenitor cell microenvironment involving adipokines, hypoxia, and oxidative stress might play a key role in the control of the self-renewal of the local pool of AT progenitor cells.
Maumus
Marie
M
Hôpital Rangueil Bat L4, BP 84225, 31432 Toulouse Cedex 04, France.
Sengenès
Coralie
C
Decaunes
Pauline
P
Zakaroff-Girard
Alexia
A
Bourlier
Virginie
V
Lafontan
Max
M
Galitzky
Jean
J
Bouloumié
Anne
A
D054392:Adipokines / Q000494:pharmacology; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D000328:Adult; D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D045604:Extracellular Fluid / Q000502:physiology*; D005260:Female; D006803:Human Development / Q000502:physiology*; D006801:Humans; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000494:pharmacology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*
D054392:Adipokines; D018952:Antigens, CD34; D017077:Culture Media, Conditioned; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D010100:Oxygen