Directing Myogenic Mesenchymal Stem Cell Differentiation
2008; Lippincott Williams & Wilkins; Volume: 103; Issue: 6 Linguagem: Inglês
10.1161/circresaha.108.184374
ISSN1524-4571
AutoresPeter E. Westerweel, Marianne C. Verhaar,
Tópico(s)Muscle Physiology and Disorders
ResumoHomeCirculation ResearchVol. 103, No. 6Directing Myogenic Mesenchymal Stem Cell Differentiation Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBDirecting Myogenic Mesenchymal Stem Cell Differentiation Peter E. Westerweel and Marianne C. Verhaar Peter E. WesterweelPeter E. Westerweel From the Department of Vascular Medicine (P.E.W., M.C.V.), University Medical Center Utrecht; and Department of Internal Medicine (P.E.W.), St. Antonius Hospital, Nieuwegein, The Netherlands. and Marianne C. VerhaarMarianne C. Verhaar From the Department of Vascular Medicine (P.E.W., M.C.V.), University Medical Center Utrecht; and Department of Internal Medicine (P.E.W.), St. Antonius Hospital, Nieuwegein, The Netherlands. Originally published12 Sep 2008https://doi.org/10.1161/CIRCRESAHA.108.184374Circulation Research. 2008;103:560–561Vascular smooth muscle cells (SMCs) play an important role in the embryonic and postnatal development and remodeling of blood vessels. In mature vasculature, SMCs regulate the vascular tone and, thereby, the blood pressure and blood distribution. SMCs are also involved in pathological vascular conditions, such as atherosclerosis, hypertension, and intima hyperplasia. SMCs retain a high degree of plasticity after differentiation, and their structure and functional characteristics may be modulated in response to external stimuli.1 Understanding cardiovascular disease requires understanding myogenic differentiation. Mesenchymal stem cells (MSCs) are multipotent stem cells that can be induced to differentiate into SMCs but may also commit to adipocytic, cardiomyogenic, chondrogenic, endothelial, neuronal, or osteoblastic differentiation. MSCs provide an opportunity to study signaling involved in SMC lineage differentiation.2,3MSCs can be obtained from various accessible sources such as bone marrow and adipose tissue and have a high proliferation capacity allowing rapid expansion ex vivo.3 This makes MSCs an attractive source for tissue engineering strategies, including SMCs generated from MSCs. SMCs may be used for the formation of contractile layers in, for example, tissue engineered urinary bladders and arterial grafts. In addition, direct cell transplantation using MSCs is under investigation for treating cardiovascular disease such as myocardial ischemia, in which injected MSCs have been shown to incorporate, adopt a SMC phenotype, and enhance neovascularization.4,5 A major challenge in using MSCs for tissue engineering or therapeutic cell transplantation is to direct their differentiation toward the desired lineage and to have the cells retain this phenotype. This further stresses the importance of understanding the pathways involved in myogenic differentiation of MSCs. In this issue of Circulation Research, Jeon et al present novel data on the mechanisms involved in sphingosylphosphorylcholine (SPC)-induced SMC differentiation of adipose tissue–derived MSCs.6SPC is a metabolite of the membrane-phospholipid sphingomyelin. Activated platelets are thought to be the major source of SPC in vivo, and SPC is found in substantial concentrations in blood plasma. Similar to other sphingolipid-derived products, SPC acts as a regulatory signaling messenger.7 SPC has been shown to stimulate neuronal and cardiac differentiation of embryonic stem cells8 and vascular network formation by endothelial cells.9 In mature vascular SMCs, SPC stimulates the contractility and migration through actin remodeling.10–12 Jeon et al have previously demonstrated that SPC induces differentiation of human adipose tissue–derived MSCs to SMCs.13Binding of SPC results in activation of several signal transduction pathways in MSCs. In their previous work, Jeon et al have shown that exposing MSCs to SPC induces activation of the extracellular signal-regulated kinase (ERK) isoform of the mitogen-activated protein kinase (MAPK).13,14 MAPK/ERK activation affects various cellular processes, and, in SPC-stimulated MSCs, this results in delayed phosphorylation of Smad2 and increased secretion of transforming growth factor (TGF)-β.14 TGF-β itself is a potent inducer of myogenic differentiation of MSCs,13,15 and its release may thus further stimulate differentiation via an autocrine mechanism. Blocking either MAPK/ERK, Smad2, or TGF-β signaling abrogated SPC-induced SMC differentiation.14,15In their present study, the authors expand on these observations and now show that SPC-induced SMC differentiation of MSCs is also dependent on the activation of the RhoA/Rho-kinase pathway.6 Interestingly, they find that this involves increased expression and nuclear translocation of myosin-related transcription factor (MRTF)-A. MRTF is known to be involved in SMC differentiation in other cell types.16 MRTF-A is a member of the myocardin family of proteins that includes myocardin, MRTF-A, and MRTF-B. These serve as cofactors for serum-response factor (SRF).16,17 SRF is a potent transcription factor that binds to the CArG DNA boxes, which are essential for expression of many skeletal, cardiac, and smooth muscle genes such as SM22-α, h1-calponin, αSMA, and smoothelin-A.16,18 Pretreatment of MSCs with small interfering RNA for SRF,13 myocardin,13 or MRTF-A6 inhibits SMC differentiation.Although the expression and nuclear translocation of SRF and its cofactors is considered to be specific for myogenic differentiation,1 the individual upstream pathways involving MAPK/ERK, RhoA/Rho-kinase, and TGF-β signaling are not. For example, neuronal differentiation of MSCs was found to also be critically dependent on activation of MAPK/ERK,19 and, in apparent contrast to the findings of Jeon et al, inhibition of MAPK/ERK activation in bone marrow MSCs was shown to induce rather than suppress spontaneous SMC differentiation.20 Therefore, how the various pathways interact to result in a commitment to the myogenic lineage remains to be further elucidated.Induction of SMC differentiation of MSCs by SPC has several potential implications in vivo. Interestingly, MSCs have been shown to home to sites of vascular injury in various experimental studies.21 At such sites of injury, SPC levels may also be particularly elevated by the presence of activated platelets generating SPC.7 It could therefore be speculated that exposition to SPC of local or circulation-derived MSCs may be a physiological cue to induce SMC generation for augmentation of wound healing.22 Such differentiation would also bring a risk for adverse vascular remodeling as proliferation of SMCs is involved in atherosclerosis and neointima-formation. Indeed, SMCs in atherosclerotic and neointimal lesions were found to be in part circulation-derived.23The effects of SPC on MSCs may also be of importance for clinical strategies involving cell transplantation. Importantly, the authors show that the MSCs induced to differentiate with SPC do not only express proteins typical for vascular SMCs but also verify that the differentiated cells have functional L-type calcium channels and calcium-dependent potassium channels, providing the cells an ability for contraction. This supports that differentiation to a fully functional smooth muscle cell phenotype was successfully achieved using SPC.A particularly interesting point is the observed robust upregulation of myocardin. Besides promoting myogenic gene expression, myocardin was recently shown to also enhance telomerase activation, thereby contributing to maintaining a "myogenic stemness" in developing MSCs.24 In addition, improved augmentation of myocardial recovery after ischemia was observed using MSCs overexpressing myocardin.25 Therefore, upregulating myocardin may enhance the therapeutic potential of MSCs for cell transplantation. If using SPC to direct MSC differentiation toward the myogenic lineage with upregulation of myocardin and associated factors has a similar effect remains to be established. If so, transplantation of MSCs after "pretreatment" with SPC may be a promising new strategy for the treatment of cardiovascular disease.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Sources of FundingP.E.W. is supported by ZonMw AGIKO grant 2007/12579, and M.C.V. is supported by De Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) Vidi grant 016.096.359.DisclosuresNone.FootnotesCorrespondence to Peter E. Westerweel, MD, PhD, Department of Vascular Medicine, G02.405, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. E-mail [email protected] References 1 Owens GK, Kumar MS, Wamhoff BR. Molecular regulation of vascular smooth muscle cell differentiation in development and disease. 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