Interleukin-6 maintains bone marrow-derived mesenchymal stem cell stemness by an ERK1/2-dependent mechanism.
Adult human mesenchymal stem cells (MSCs) hold promise for an increasing list of therapeutic uses due to their ease of isolation, expansion, and multi-lineage differentiation potential. To maximize the clinical potential of MSCs, the underlying mechanisms by which MSC functionality is controlled must be understood. We have taken a deconstructive approach to understand the individual components in vitro, namely the role of candidate "stemness" genes. Our recent microarray gene expression profiling data suggest that interleukin-6 (IL-6) may contribute to the maintenance of MSCs in their undifferentiated state. In this study, we showed that IL-6 gene expression is significantly higher in undifferentiated MSCs as compared to their chondrogenic, osteogenic, and adipogenic derivatives. Moreover, we found that MSCs secrete copious amounts of IL-6 protein, which decreases dramatically during osteogenic differentiation. We further evaluated the role of IL-6 for maintenance of MSC "stemness," using a series of functional assays. The data showed that IL-6 is both necessary and sufficient for enhanced MSC proliferation, protects MSCs from apoptosis, inhibits adipogenic and chondrogenic differentiation of MSCs, and increases the rate of in vitro wound healing of MSCs. We further identified ERK1/2 activation as the key pathway through which IL-6 regulates both MSC proliferation and inhibition of differentiation. Taken together, these findings show for the first time that IL-6 maintains the proliferative and undifferentiated state of bone marrow-derived MSCs, an important parameter for the optimization of both in vitro and in vivo manipulation of MSCs.
Pricola
Katie L
KL
Cartilage Biology and Orthopaedics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA.
Kuhn
Nastaran Z
NZ
Haleem-Smith
Hana
H
Song
Yingjie
Y
Tuan
Rocky S
RS
D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology*; D002070:Butadienes / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016895:Culture Media, Serum-Free; D019610:Cytoprotection / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D008875:Middle Aged; D009570:Nitriles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects
D002070:Butadienes; D016895:Culture Media, Serum-Free; D015850:Interleukin-6; D009570:Nitriles; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C113580:U 0126; D048049:Extracellular Signal-Regulated MAP Kinases