Differentiation of bone marrow mesenchymal stem cells into the smooth muscle lineage by blocking ERK/MAPK signaling pathway.
Smooth muscle cells (SMCs) are major components of blood vessels and other hollow visceral organs required for tissue engineering of these organs. This study aims to evaluate whether adult bone marrow-derived mesenchymal stem cells (BMMSCs), multipotent cells, can be converted into SMCs. We examined the ERK/MAPK pathway as it exerts anti-myogenic signals in SMCs. Undifferentiated BMMSCs express most SMC marker genes, albeit mainly at low levels, except smooth muscle myosin heavy chain (SMMHC), the most definitive marker of differentiated SMC. The treatment of BMMSC with MEK inhibitor up-regulated the expression of alpha-smooth muscle actin (ASMA), h-caldesmon, and SMMHC in BMMSC in low serum condition. MEK inhibitor-treated BMMSC also contracted a collagen gel in response to endothelin. Interestingly, inhibition of MEK induced myocardin expression in BMMSC. In conclusion, BMMSCs treated MEK inhibitor gain a SMC-like phenotype with ligand-induced cell contractility to endothelin in vitro. This approach has obvious implications for cell therapeutics and tissue engineering of hollow visceral organs such as blood vessels.
Tamama
Kenichi
K
Department of Pathology, Ohio State University Medical Center, Columbus, Ohio 43210, USA. kenichi.tamama@osumc.edu
Sen
Chandan K
CK
Wells
Alan
A
D000199:Actins / Q000378:metabolism; D000077214:Becaplermin; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D016232:Endothelins / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism; D005782:Gels; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D024510:Muscle Development / Q000187:drug effects; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism; D000099251:Myocardin
D000199:Actins; D000077214:Becaplermin; D002148:Calmodulin-Binding Proteins; D003094:Collagen; D016232:Endothelins; D048049:Extracellular Signal-Regulated MAP Kinases; D005782:Gels; D008840:Microfilament Proteins; D009124:Muscle Proteins; D018995:Myosin Heavy Chains; D009687:Nuclear Proteins; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D000099251:Myocardin; C494112:ELK1 protein, human; C051615:transgelin