IFATS collection: Fibroblast growth factor-2-induced hepatocyte growth factor secretion by adipose-derived stromal cells inhibits postinjury fibrogenesis through a c-Jun N-terminal kinase-dependent mechanism.
Adipose-derived stem/stromal cells (ASCs) not only function as tissue-specific progenitor cells but also are multipotent and secrete angiogenic growth factors, such as hepatocyte growth factor (HGF), under certain circumstances. However, the biological role and regulatory mechanism of this secretion have not been well studied. We focused on the role of ASCs in the process of adipose tissue injury and repair and found that among injury-associated growth factors, fibroblast growth factor-2 (FGF-2) strongly promoted ASC proliferation and HGF secretion through a c-Jun N-terminal kinase (JNK) signaling pathway. In a mouse model of ischemia-reperfusion injury of adipose tissue, regenerative changes following necrotic and apoptotic changes were seen for 2 weeks. Acute release of FGF-2 by injured adipose tissue was followed by upregulation of HGF. During the adipose tissue remodeling process, adipose-derived 5-bromo-2-deoxyuridine-positive cells were shown to be ASCs (CD31-CD34+). Inhibition of JNK signaling inhibited the activation of ASCs and delayed the remodeling process. In addition, inhibition of FGF-2 or JNK signaling prevented postinjury upregulation of HGF and led to increased fibrogenesis in the injured adipose tissue. Increased fibrogenesis also followed the administration of a neutralizing antibody against HGF. FGF-2 released from injured tissue acts through a JNK signaling pathway to stimulate ASCs to proliferate and secrete HGF, contributing to the regeneration of adipose tissue and suppression of fibrogenesis after injury. This study revealed a functional role for ASCs in the response to injury and provides new insight into the therapeutic potential of ASCs.
Suga
Hirotaka
H
Department of Plastic Surgery, University of Tokyo, Japan.
Eto
Hitomi
H
Shigeura
Tomokuni
T
Inoue
Keita
K
Aoi
Noriyuki
N
Kato
Harunosuke
H
Nishimura
Satoshi
S
Manabe
Ichiro
I
Gonda
Koichi
K
Yoshimura
Kotaro
K
D000273:Adipose Tissue / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D000328:Adult; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D010641:Phenotype; D015427:Reperfusion Injury / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D014945:Wound Healing / Q000187:drug effects
D016222:Fibroblast Growth Factor 2; D017228:Hepatocyte Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases