Mounting evidence indicates that the regenerative effect of mesenchymal stem cells in skeletal muscle is related to the secretion of factors that stimulate resident myogenic cells. However, the environmental cues that affect the secreted factors of mesenchymal stem cells are not well understood. A recent publication demonstrated that secretion of factors is dependent on cell substrate, with mesenchymal stem cells grown on laminin providing more pro-myogenic factors than those grown on collagen, and that cellular strain may also play a role. Conditioned media from mesenchymal stem cells grown on laminin and subjected to strain provided the quickest and largest stimulation to myogenic cell proliferation. The influence of cell substrate and mechanical perturbation on mesenchymal stem cells therefore appears key to secretion of factors that support myogenesis

Smith, Lucas R

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Influencing the secretion of myogenic factors from mesenchymal stem cells

Lucas R Smith

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Smith Stem Cell Research & Therapy 2014, 5:96http://stemcellres.com/content/5/4/96COMMENTARYInfluencing the secretion of myogenic factorsfrom mesenchymal stem cellsLucas R SmithSee related research by De Lisio et al., http://stemcellres.com/content/5/3/74AbstractMounting evidence indicates that the regenerativeeffect of mesenchymal stem cells in skeletal muscle isrelated to the secretion of factors that stimulateresident myogenic cells. However, the environmentalcues that affect the secreted factors of mesenchymalstem cells are not well understood. A recent publicationdemonstrated that secretion of factors is dependent oncell substrate, with mesenchymal stem cells grown onlaminin providing more pro-myogenic factors thanthose grown on collagen, and that cellular strain mayalso play a role. Conditioned media from mesenchymalstem cells grown on laminin and subjected to strainprovided the quickest and largest stimulation tomyogenic cell proliferation. The influence of cellsubstrate and mechanical perturbation on mesenchymalstem cells therefore appears key to secretion of factorsthat support myogenesis.to a diseased environment. In skeletal muscle the dis-IntroductionSkeletal muscle’s robust ability to regenerate is compro-mised in a myriad of diseases, ranging from geneticmuscular dystrophies to sarcopenia, with few therapeuticoptions available for those suffering from these condi-tions. One commonality among these conditions is analteration in the local muscle environment, particularlyprolific extracellular matrix components and fibrosis.The primary cell responsible for regeneration of skeletalmuscle is the tissue-resident satellite cell; however, thein vivo cues that lead to satellite cell-based regenerationare not completely understood. Mesenchymal stem/stro-mal cells (MSCs) are increasingly being viewed as an in-stigator for satellite cell activation and coordinator ofmuscle regeneration [1,2]. De Lisio and colleagues [1]Correspondence: smithlu@dental.upenn.eduDepartment of Anatomy and Cell Biology, School of Dental Medicine,University of Pennsylvania, 2040 S. 40th Street, Philadelphia, PA 19104, USA© Smith; licensee BioMed Central Ltd. Thmonths following its publication. After this timLicense (http://creativecommons.org/licenses/medium, provided the original work is propercreativecommons.org/publicdomain/zero/1.0/2014have recently investigated how the extracellular matrixand mechanical environment of MSCs refines their abil-ity to promote myogenesis.MSCs play a role in homeostasis and regeneration inmany tissues, and they have been shown to inhibit degen-eration and enhance regeneration in a variety of tissues,including skeletal muscle [3]. MSCs present an excitingpotential for cell-based therapy due to their ease of isola-tion and immune privileged status and their vigorousability to expand in culture. MSCs may support tissue re-generation through direct differentiation due to theirmulti-lineage potential, but more likely act via secretion offactors that stimulate native tissue repair processes [4].Within skeletal muscle the variety of supportive mesen-chymal progenitor cells has been an active area of research[2]. While the possibility that these cells become myogenicremains, their potential to regulate muscle regenerationthrough secretion of pro-myogenic factors is clear.What is less clear is how the MSC secrotome respondseased environment is often associated with fibrosis, withMSCs exposed to an abundance of collagen. Skeletalmuscle is a highly dynamic tissue in which the local en-vironment includes frequent large strains that have thepotential to manipulate the MSCs as well. A study by DeLisio and colleagues [1] in the previous issue of StemCell Research & Therapy investigated the effect of thestrain and substrate on the ability of MSCs to promotemyogenesis. The authors isolated MSCs resident in skel-etal muscle of transgenic mice overexpressing α7 integ-rin, providing greater cell yields compared to wild-typemice [5]. The MSCs were cultured on either laminin orcollagen I and subsets of each were subjected to a 5 hourstrain protocol. Neither substrate nor strain had an im-pact on the proliferation of the MSCs. While none ofthe MSCs differentiated toward a muscle fate, thosegrown on laminin did express increased levels of myo-genic factors (Myf5, MyoD, and myogenin). Additionally,growth and inflammatory factor expression by MSCse licensee has exclusive rights to distribute this article, in any medium, for 12e, the article is available under the terms of the Creative Commons Attributionby/4.0), which permits unrestricted use, distribution, and reproduction in anyly credited. The Creative Commons Public Domain Dedication waiver (http://) applies to the data made available in this article, unless otherwise stated.Smith Stem Cell Research & Therapy Page 2 of 22014, 5:96http://stemcellres.com/content/5/4/96was reduced on collagen substrates, which mimic the fi-brotic muscle environment, including vascular endothelialgrowth factor A, interleukin-6, and NF-κB. Surprisingly,transforming growth factor β1 was also decreased on thecollagen substrate despite its hypothesized role as a keycomponent of the positive feedback loop leading toprogressive muscle fibrosis [6]. The collagen substrate alsoled to a decrease in laminin expression; however, theexpression of collagen was not affected by substrate. Theauthors hypothesize that these changes in expression maybe mediated through activation of focal adhesion kinase(FAK), a known player in mechanotransduction [7]. Whilep-FAK did increase on stretched laminin substrate, this re-sult was not observed in myogenic factor expression, im-plicating other methods for signal transduction drivingMSCs to secrete myogenic factors. This investigation laysa foundation to test other factors secreted by MSCs thatpromote muscle regeneration, such as matrix metallopro-teinases [8], for their dependence on substrate and strain.Undoubtedly the milieu of factors being secreted bysupportive cells, including MSCs, in skeletal muscle iscomplex. While the study of which individual secretedfactors play a role progresses, assessing the gamut offactors is necessary to delimit the potential of environ-mental factors in MSCs in support of myogenesis. Byapplying conditioned media from MSCs grown in theenvironments outlined previously to myoblasts, a rangeof factors and their interactions have been observed.MSCs grown on laminin and subjected to stretch pro-duced media that 24 hours after transfer to myoblastculture increased the proliferation of myoblasts com-pared to conditioned media from other MSC environ-ments. This result fits in well with the activation of FAKobserved in MSCs on stretched laminin. However, after48 hours the number of myoblasts was greatest when ex-posed to media from MSCs grown on collagen. The incon-sistent effect on proliferation with time confuses definitionof the optimal substrate for MSCs to support myoblastproliferation long term. Myoblast proliferation is seen asthe major factor altered by MSC conditioned media assigns of hypertrophy in myotubes were not present.De Lisio and colleagues have provided strong evidencethat the secretome of MSCs is influenced by the substratethey are attached to and may also be regulated by strain.The alteration of secreted factors by substrate and strainhas effects on myoblast proliferation, but additional workis required to optimize the environment in which MSCssupport myogenesis. There are also indirect avenues forthe secretome of MSCs to exert influence on myoblasts, asevidenced by strain inducing MSCs to produce factors pro-moting vessel remodeling [9]. De Lisio and colleagues havejust cracked the door open on the interaction between themuscle MSC environment and their secretion of pro-myogenic factors, as a multitude of further interactions arepossible. For example, insulin-like growth factor 1 has beenshown to be a potent activator of myogenesis [10] and en-hance repair when overexpressed by MSCs [11]. Eventuallythese lessons learned in culture will need to be transferredto an in vivo system. A key issue in the development ofMSCs for therapeutic purposes is how quickly the MSCsrespond to these environmental cues. Will pre-conditionedMSCs maintain their pro-myogenic secretions onceinjected into a diseased muscle environment? Continuedefforts such as these to study the effect of local environ-ments on the multitude of cells in skeletal muscle will benecessary to tailor treatments to diseased muscle.AbbreviationsFAK: Focal adhesion kinase; MSC: Mesenchymal stem/stromal cell.Competing interestsThe author declares that they have no competing interests.AcknowledgementsThis work was supported by NIH Training Grant from the PennsylvaniaMuscle Institute (AR053461) and the Wellstone Muscular Dystrophy ResearchCenter (AR052646).Published:References1. De Lisio M, Jensen T, Sukiennik RA, Huntsman HD, Boppart M: Substrateand strain alter the muscle-derived mesenchymal stem cell secretome topromote myogenesis. Stem Cell ResTher 2014, 5:74.2. Yin H, Price F, Rudnicki MA: Satellite cells and the muscle stem cell niche.Physiol Rev 2013, 93:23–67.3. Boppart MD, De Lisio M, Zou K, Huntsman HD: Defining a role for non-satellite stem cells in the regulation of muscle repair following exercise.Front Physiol 2013, 4:310.4. Ranganath SH, Levy O, Inamdar MS, Karp JM: Harnessing the mesenchymalstem cell secretome for the treatment of cardiovascular disease. CellStem Cell 2012, 10:244–258.5. Valero MC, Huntsman HD, Liu J, Zou K, Boppart MD: Eccentric exercisefacilitates mesenchymal stem cell appearance in skeletal muscle. PloSOne 2012, 7:e29760.6. Mann CJ, Perdiguero E, Kharraz Y, Aguilar S, Pessina P, Serrano AL, Munoz-Canoves P: Aberrant repair and fibrosis development in skeletal muscle.Skelet Muscle 2011, 1:21.7. Huang CH, Chen MH, Young TH, Jeng JH, Chen YJ: Interactive effects ofmechanical stretching and extracellular matrix proteins on initiatingosteogenic differentiation of human mesenchymal stem cells. J CellBiochem 2009, 108:1263–1273.8. Sassoli C, Nosi D, Tani A, Chellini F, Mazzanti B, Quercioli F, Zecchi-OrlandiniS, Formigli L: Defining the role of mesenchymal stromal cells on theregulation of matrix metalloproteinases in skeletal muscle cells. Exp CellRes 2014, 323:297–313.9. Huntsman HD, Zachwieja N, Zou K, Ripchik P, Valero MC, De Lisio M,Boppart MD: Mesenchymal stem cells contribute to vascular growth inskeletal muscle in response to eccentric exercise. Am J Physiol Heart CircPhysiol 2013, 304:H72–H81.10. Barton ER: The ABCs of IGF-I isoforms: impact on muscle hypertrophyand implications for repair. Appl Physiol Nutrition Metab 2006, 31:791–797.11. Haider H, Jiang S, Idris NM, Ashraf M: IGF-1-overexpressing mesenchymalstem cells accelerate bone marrow stem cell mobilization via paracrineactivation of SDF-1alpha/CXCR4 signaling to promote myocardial repair.Circ Res 2008, 103:1300–1308.Cite this article as: Smith: Influencing the secretion of myogenic factorsfrom mesenchymal stem cells. Stem Cell Research & Therapy13 Aug 201410.1186/scrt4852014, 5:96

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