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Role of stem/progenitor cells in reparative disorders Pretheeban, Thavaneetharajah; Lemos, Dario R; Paylor, Benjamin; Zhang, Regan-Heng; Rossi, Fabio M Dec 27, 2012

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REVIEW Open AccessRole of stem/progenitor cells in reparativedisordersThavaneetharajah Pretheeban, Dario R Lemos, Benjamin Paylor, Regan-Heng Zhang and Fabio M Rossi*AbstractAdult stem cells are activated to proliferate and differentiate during normal tissue homeostasis as well as in diseasestates and injury. This activation is a vital component in the restoration of function to damaged tissue via eithercomplete or partial regeneration. When regeneration does not fully occur, reparative processes involving anoverproduction of stromal components ensure the continuity of tissue at the expense of its normal structure andfunction, resulting in a “reparative disorder”. Adult stem cells from multiple organs have been identified as beinginvolved in this process and their role in tissue repair is being investigated. Evidence for the participation ofmesenchymal stromal cells (MSCs) in the tissue repair process across multiple tissues is overwhelming and their rolein reparative disorders is clearly demonstrated, as is the involvement of a number of specific signaling pathways.Transforming growth factor beta, bone morphogenic protein and Wnt pathways interact to form a complexsignaling network that is critical in regulating the fate choices of both stromal and tissue-specific resident stem cells(TSCs), determining whether functional regeneration or the formation of scar tissue follows an injury. A growingunderstanding of both TSCs, MSCs and the complex cascade of signals regulating both cell populations have,therefore, emerged as potential therapeutic targets to treat reparative disorders. This review focuses on recentadvances on the role of these cells in skeletal muscle, heart and lung tissues.Keywords: Fibrosis, Fatty degeneration, Heterotopic ossification, Tissue specific stem cells, Mesenchymal stromalcells, TGFβ, BMP, WntReviewIntroductionTissue repair post-injury or during disease culminates ineither complete restoration of tissue integrity, definedhere as regeneration, or in a process that leads to thegeneration of stromal structures that replace functionaltissue. These structures, while vital in ensuring tissuecontinuity, do not support, and in some instances eveninterfere with, tissue or organ function. The establish-ment of these stromal scars is referred herein as “repair”,and conditions in which they become predominant arecalled “reparative disorders”. This term encompassesdiseases or symptoms exhibited during the repairprocess of damaged tissues that have been described inthe literature since the early nineteenth century, includingadipocyte accumulation (fatty degeneration), ectopic boneformation and fibrous tissue deposition [1-3]. In thecontext of mammalian biology, tissue regeneration is anessential process for restoring structure and function oftraumatized organs. Regeneration of tissues is typicallyaccompanied by acute or chronic inflammation caused bythe disease or trauma, and involves the coordinated inter-action among multiple cell types, including tissue specificstem/ progenitor cells (TSCs), mesenchymal stromal cells(MSCs) and immune cells. Many of the same cell typesinvolved in regeneration also contribute to repair, suggest-ing that aberrant environmental cues and alterations ofthe signaling networks between these cells are central tothe establishment of reparative disorders [4].Several sources have been proposed for the progeni-tors involved in reparative disorders, including localsources, such as the damaged tissues themselves, andsystemic sources, such as the bone marrow [5]. Locally,both tissue specific stem cells and ubiquitous mesenchy-mal and endothelial progenitors have been implicated in* Correspondence: fabio@brc.ubc.caThe Biomedical Research Centre, The University of British Columbia,Vancouver, BC V6T 1Z3, Canada© 2012 Pretheeban et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of theCreative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use,distribution, and reproduction in any medium, provided the original work is properly cited.Pretheeban et al. Fibrogenesis & Tissue Repair 2012, 5:20http://www.fibrogenesis.com/content/5/1/20the development of the cellular effectors of repair: fi-brotic matrix producing cells, adipocytes and osteocytes.Systemically, a role has been proposed for bone marrowderived cells reaching the repairing tissues through thebloodstream. Here, we review the evidence concerningthese different types of stem cells and, in particular, therole of TSCs and MSCs in reparative disorders. We alsoprovide an overview of the signaling pathways mediatingtheir interactions.The three most commonly occurring outcomes of rep-arative disorders are fibrosis, fatty degeneration and het-erotopic ossification. Fibrosis is a defining characteristicin most reparative disorders and can take place in nearlyevery tissue. In fibrosis, damaged structures are grad-ually replaced by collagen-rich connective tissueresulting in anatomical anomalies as well as reducedfunctional capacities. The poorly defined fibroblast ormyofibroblast, the effector cell components of con-nective tissue, is thought to be responsible for produ-cing excess collagen and other extracellular matrix(ECM) proteins [6]. These same processes, however,also take place during normal regeneration, and arelikely to be critical for its success. Another type ofcommon reparative disorder is the accumulation of fatin damaged tissues leading to “fatty degeneration” andloss of function [4-6]. Usually, fat is found in newlyformed adipocytes infiltrating the tissue, most oftenassociated with concurrent fibrotic matrix deposition,and in these cases it is clearly associated with injuriesand defective repair processes [7-9]. Finally, heteroto-pic ossification, also known as ectopic bone formation,is another frequent reparative complication that takesplace in the context of excessive trauma, surgery,wounds and burns. While non-hereditary and heredi-tary extra-skeletal bone formation is discussed in detailelsewhere [10,11], here we will focus only on thesource of osteogenic cells in aberrant repair processes.Tissue resident stromal cellsIn the adult organism, fibroblasts, adipocytes and osteo-cytes are thought to be generated from the same multi-potent mesenchymal progenitors. These progenitors,officially termed mesenchymal stromal cells (MSCs) in apositional paper from the International Society for Cel-lular Therapeutics [12] continue to be referred to asmesenchymal stem cells [13], despite the lack of clearexperimental evidence supporting their ability to self-renew and satisfy the most basic definition of a stem cell[14]. The accumulation of these mature cell types in tis-sues that have failed to properly regenerate suggests thatalterations in the function of MSCs may represent acommon thread underlying reparative disorders [15].While a minimal set of markers defining an MSC hasbeen agreed upon [12], expression of these markers isclearly heterogeneous both in vivo and in vitro and doesnot currently allow their prospective purification. Inaddition, while MSCs retain a similar developmentalpotential in most tissues, the expression of specificmarkers may vary depending on their specific anatom-ical location, a reality that has hindered the propercharacterization of stromal progenitors. To date, themost reliable characteristic of stromal progenitors isthe ability to produce fibroblastic colonies and, underthe appropriate culture conditions, to differentiate inadipocytes, chondrocytes and osteogenic cells. The gen-eration of additional cell types, such as endotheliumand skeletal muscle, has been reported, but no consen-sus exists on whether such expanded developmentalpotential is actually observed in physiological condi-tions. Indeed, in the absence of specific markers toidentify them in situ, elucidating the role of MSCs inthe maintenance of differentiated tissues, such as boneand fat depots in vivo, has been difficult and their im-portance is as yet unclear. Another role for this celltype that has emerged over the years has spurred theirtherapeutic exploitation in ex vivo delivery approaches,and lies in their ability to provide trophic support tomultiple cell types following tissue damage.Almost all postnatal organs and tissues contain MSCs[16], and the list of resident stromal cells involved in tis-sue homeostasis and repair now includes multiple celltypes, such as pericytes in multiple tissues [17,18], fibro-adipogenic progenitors (FAPs) in muscle and adipose tis-sues [19,20], adipose precursor cells in skin [21] andmyo-fibroblasts in the liver, kidneys and lungs [22]. It isunclear whether these are truly distinct cell types, or ifthey, rather, represent a diffused stromal progenitor sys-tem comprised of cells that display different propensityto spontaneously differentiate along specific lineages, butpossess a common underlying developmental potentialthat can be revealed by exposure to the appropriatestimuli. In addition to these ubiquitous progenitors, tis-sue fibroblasts have also been proposed to arise from cir-culating bone marrow cells or, in specific organs, fromepithelial-mesenchymal transition (EMT) (see reviews[23,24]); the controversial evidence supporting theseclaims will be discussed below. The multiple proposedsources of fibrogenic cells in adult life are schematicallydepicted in Figure 1.Despite the uncertainties and controversies stemmingfrom their incomplete characterization, recent literatureclearly supports a role for MSCs not only in immuno-modulation, trophic support, angiogenesis and otherprocesses associated with successful tissue regeneration,but also in reparative disorders, such as fibrosis and fattydegeneration [25-27]. Here we discuss recent advanceson the role of MSCs in skeletal and cardiac muscle aswell as lung reparative disorders.Pretheeban et al. Fibrogenesis & Tissue Repair 2012, 5:20 Page 2 of 12http://www.fibrogenesis.com/content/5/1/20The role of tissue-resident MSCs and TSCs in reparativedisordersSkeletal muscle – an ideal regenerative/degenerative modelsystemSkeletal muscle, like many other organs, contains stro-mal cells that are active following injury in both healthyanimals and disease models. In addition, stromal cellsare believed to play an essential role in muscle develop-ment [28]. These stromal cells are found in the muscleinterstitium as well as associated with blood vessels(Figure 2). While often found in a perivascular position,they have been reported not to express typical pericyticmarkers, such as NG2 [29,30]. In mice, these cells arecapable of spontaneously differentiating along the fibro-genic and adipogenic lineages in vitro, and have, therefore,been provisionally called fibro-adipogenic progenitors(FAPs) [19]. FAPs can be isolated as CD45-/CD31-/α7/CD34+/Sca-1+/PDGFRα+ cells. Cells expressing fibroblastmarkers (ER-TR7/FSP1/αSMA) or adipogenic markers,such as perilipin, arise from individual multipotent pro-genitors contained in this population. We and others[19,31] have further demonstrated that the fate of theseprogenitors is heavily dependent on the environmentwithin which they reside. This local microenvironmentdictates whether these cells provide trophic support tosatellite cells, the endogenous myogenic stem cells, toyield complete regeneration of injured muscle or whetherthey generate the components of the fibro-fatty tissueinfiltrates often found in degenerating muscle tissue. Arole for these cells in the efficient regeneration of muscleis also supported by depletion experiments relaying on theexpression of CRE recombinase under the control of thetranscription factor Tcf4 [28]. This approach led to the de-pletion of only about 40% of the cells, and highly efficientdeletion of stromal progenitors has yet to be achieved inany organ. More recently, also in support of a paracrineeffect of MSCs, Lavasani et al. [32] reported that musclederived stem/progenitor cells (MDSPCs), essentially stro-mal cells isolated from young mice, were able to improvedegenerative changes in aged mice and observed a correl-ation between MDSPC abundance and better muscle fibermaturation post injury.Skeletal muscle resident FAPs are quiescent in healthytissue, but quickly respond to damage by enteringBMHeartSkeletal MuscleLungEpithelium/EndotheliumCirculating Fibrocytes EMT/EndMTTissue Resident MSCsEctopic OssificationFatty DegenerationFibrosisReparative DisordersFigure 1 Potential sources of MSCs in tissue repair. During injury or disease tissue-resident MSCs (mesenchymal stromal/stem cells) canexpand and provide trophic support for regeneration and/or differentiate to produce fibrosis, fatty degeneration or ectopic ossification or acombination of these. In addition, contribution to the fibrogenic cell pool by circulating “fibrocytes” originated from BM (bone marrow) andeither EMT/EndMT (epithelial-mesenchymal transition/endothelial-mesenchymal transition) are proposed even though their existence, as well asthe impact of their contribution to the deposition of fibrotic matrix, is controversial.Pretheeban et al. Fibrogenesis & Tissue Repair 2012, 5:20 Page 3 of 12http://www.fibrogenesis.com/content/5/1/20proliferation and expanding to infiltrate the extracellularspace between myofibers, where they presumably carryout their trophic support function. Following this periodof expansion, and at a time in which myogenic progeni-tors are differentiating to regenerate myofibers, the ex-cess FAPs generated during the expansion phase quicklydisappear and the cells return to quiescence. This, how-ever, is not the case in degenerative disease or duringaging. In situations where regeneration fails, FAPs persistand generate fibrous/fatty tissue that, while maintainingstructural integrity, hinders function and subsequent re-generation [33,34]. It is important to note that FAPshave been reported to be the only source of collagenproducing cells in regenerating skeletal muscle [35],clearly pointing to these cells as the main origin of fibro-sis. While strong support exists for both the trophic roleof FAPs and their role on tissue degeneration, the signalsregulating their growth, survival and differentiation arestill unknown. As these signals represent promisingtherapeutic targets for the treatment of acute andchronic injuries, they are the objects of intense investiga-tion [36].Role of skeletal muscle derived MSCs in heterotopicossificationHeterotopic ossification is a common finding followingsevere or repeated soft tissue injuries, usually associatedwith fibrotic or fibro-fatty degeneration. The involve-ment of MSC-like progenitors in this process issupported by observations in war-traumatized patients,whose muscle are found to contain cells capable of produ-cing fibroblastic colonies and to give rise to osteoblasts,adipocytes and/or chondrocytes [37-39]. Presumably inthese instances, while a subset of local mesenchymal pro-genitors proliferate and differentiate into fibroblasts pro-ducing fibrotic matrix, some adopt a different lineagecommitment and become osteoprogenitors. They, in turn,differentiate into osteoblasts, eventually resulting inectopic bone formation [40]. Indeed, while FAPs were ori-ginally described as bipotent progenitors due to theirspontaneous differentiation along the fibrogenic and adi-pogenic lineages, recent evidence strongly supports theirrole in ectopic bone formation. Following this, earlyreports suggested that these cells could generate alkalinephosphatase positive cells [31]. More recently, [41]reported that CD31–/CD45–/PDGFRa+/Sca-1+/Tie2+ pro-genitors from skeletal muscle could generate cells expres-sing the osteoprogenitor marker osterix when exposed tobone morphogenic protein 2 (BMP2) in vitro or in a trans-plantation setting. In addition, lineage-tracing experimentsshowed that these cells were the main source of ectopiccartilage and bone when BMP2 was delivered to skeletalmuscle in vivo [41]. In these experiments, not all osteo-genic cells expressed the Tie2-CRE activated lineage-tracing marker. However, it is unclear whether this reflectsinefficient CRE mediated recombination or the participa-tion of Tie2 negative cells in this process. Supporting ourprevious results, without addition of BMP2, these cellsfailed to adopt the fate of cartilage or bone, demonstratingthat environmental cues are dictating the destiny of theseprogenitors and, thereby, the outcome of wound healing.Role of tissue-specific stem cells in skeletal muscledegenerationAlthough the role of MSCs in the development of rep-arative disorders in skeletal muscle has been clearlydemonstrated, there is also evidence implicating a roleof TSCs in modulating aberrant repair processes in thisorgan. The importance of the principal stem cell in adultmyogenesis, the satellite cell, in regeneration is wellestablished, but the relationship between these stem cellsand tissue degeneration is much more complex and notwell understood. Satellite cells reside between the myofi-bers and basement membrane of the muscle bundle [42]and unlike tissues that experience constant wear andtear, these TSCs are normally quiescent/stable, and arenot activated until prompted by injury. Quiescent satel-lite cells are identified by their expression of Pax7, apaired homeobox transcription factor partly responsiblefor survival and specification of the myogenic celllineage [43]. Although an excellent marker of all satellitecells in the wild-type adult, Pax7 is only required dur-ing the neonatal stage for satellite cell maintenance,FAPs/PDGFRA-GFP+Blood vessels/CD31+Nuclei/Toto3+Figure 2 Fibro/adipogenic progenitors (FAPs) in skeletalmuscle. Confocal image of a cluster of muscle fibers harvested fromnon-damaged muscle showing the relationship betweenmesenchymal progenitors expressing nuclear GFP under the controlof the PDGFRα locus and fiber-associated blood vessels positive forCD31 (red). Nuclei are stained blue.Pretheeban et al. Fibrogenesis & Tissue Repair 2012, 5:20 Page 4 of 12http://www.fibrogenesis.com/content/5/1/20proliferation and differentiation [44,45]. Following trau-matic myofiber damage or temporal progression of my-opathy, these satellite cells become activated andreadily proliferate, differentiate and give rise to myo-blasts, which fuse with damaged myofibers or form newmyofibers.Fibrosis is often associated with the impairment ofstem cell populations in tissues, which are observed inmany disease conditions. In skeletal muscle, fibrosis wasconsidered to be caused by dysfunctional satellite cells.Using a murine model of muscular dystrophy (MDX),Alexakis and others reported the expression of collagenin primary myoblasts [46]. They have also found colla-gen expression in C2C12, a myoblast cell line. Thesefindings indicate that satellite cells and transitionallyamplifying myoblasts might deviate from their myogenicprocess to lead fibrosis-dominated degeneration. Fur-thermore, Keller [47] has suggested that the dysregula-tion of satellite cells during neonatal muscle growth islinked to rhabdomyosarcoma, a rare form of connectivetissue tumor. Recently, in a mouse model of spinal mus-cular atrophy, mutation in the survival of motor neuron(SMN) gene is shown to affect the satellite cell’s intrinsicdifferentiation capacity, leading to a reduced efficiencyin myotube formation [48]. Moreover, the conversion ofsatellite cells from a myogenic lineage to a fibrogeniclineage is documented in aging [49] and suggested thatin aged mice, activation of the canonical Wnt signalingpathway is responsible for a pro-fibrotic phenotype.Other cases of fibrogenesis in myoblasts are alsoreported [50,51]. In addition, a recent study examiningthe stem cell function in aged people demonstrates thatan age-related impairment of satellite cells is associatedwith increased co-localization of myostatin in satellitecells of type II myofibers [52]. Thus, tissue-specific stemcells responsible for regeneration, such as satellite cellsin skeletal muscle, may also be involved in degenerativeprocesses; however, whether the triggers for degener-ation are cell autonomous or environmental influences,such as niche factors, is unknown.Tissue-resident MSCs reside in the heartIn mammals, cardiac damage is not followed by thecomplete replacement of lost cellular components but israther defined by a relatively minor capacity for regener-ation and far more robust reparative response. Lackingan ability to regenerate, the formation of a scar in atimely manner following cardiac damage or during car-diac disease is critical in allowing continued organ func-tionality. Although there is a growing body of evidencedemonstrating that the heart harbors its own populationof TSCs, the cardiac stem cells [37,38], which accountfor the limited regenerative capacity of this organ, recentevidence has suggested that, similar to other organs, itsrepair processes may be governed by a cardiac-residentpopulation of MSCs. The identification and elucidationof developmental origins of a novel population of stromalprogenitors present within the myocardium has recentlybeen reported [39], and further been demonstrated to behighly similar to MSCs derived from other tissues [40].This population of cells contains all the fibroblasticcolony-generating progenitors in the tissue, and was iso-lated based on markers essentially identical to thoseexpressed by stromal progenitors in skeletal muscle (Sca-1+/PDGFRa+/CD31–) and was further shown to originatefrom the pro-epicardium. Expression of accepted markersof MSCs (CD44, CD90, CD29 and CD105) was confirmedon these cells, which also exhibited long-term growth po-tential in culture and were reported to possess the abilityto form multiple mesodermal lineages (cardiomyocytes,endothelium, smooth muscle, adipocytes, cartilage andbone). As in skeletal muscle, in adult mice these cellsoccupy a perivascular, adventitial niche. A wider develop-mental potential encompassing elements of all germ layershas been reported for these cells upon co-transplantationwith teratoma-forming ES cells, although the fact thatfusion-induced reprogramming was not excluded in theseexperiments is a caveat. While the response of these cellsto acute or chronic damage has yet to be analyzed in de-tail, it seems likely that similar to their phenotypicallyidentical counterparts in skeletal muscle and other tissues[35,53], cardiac Sca1+, PDGFRα+ cells are a main sourceof fibrogenic cells in pathological cardiac fibrosis and thatthey participate in the formation of post-infarction scars.Tissue-resident MSCs in the lungIn lungs, an anti-fibrotic role has been reported for ex-ogenously delivered bone marrow derived MSCs, whichlikely rests on their ability to secrete trophic factors dur-ing normal regeneration. However, in keeping with whatis reported in other tissues, lung derived/resident MSCs(LR-MSCs) have also been associated with fibrogenesisand aberrant tissue repair in lung injuries, such as trans-plantation surgery [54]. Lama and others first isolatedLR-MSCs from the bronchoalveolar lavage fluid of lungtransplantation patients [55]. These cells exhibitedplastic adherence, formation of colony forming unit –fibroblasts (CFU-Fs), multipotency and expression of acombination of typical MSC surface markers CD44,CD73, CD90 and CD105 [55,56]. In most of the studiesin which LR-MSCs exhibited a progressive fibroticphenotype, investigators have used chronic injurymodels. Studies describing a positive role for exogen-ous MSCs, however, mainly relied on acute injurymodels, supporting the notion that these cells may playdifferent roles in different settings.It has been suggested that bi-directional crosstalk be-tween stromal progenitors and cells involved in immunePretheeban et al. Fibrogenesis & Tissue Repair 2012, 5:20 Page 5 of 12http://www.fibrogenesis.com/content/5/1/20responses may control both the fate and function of LR-MSCs and vice versa. Jun and others recently characterizeda population of lung-derived stromal cells (Hoechstdim/CD45-), which attenuated bleomycin-induced lung fibrosisand modulated local immune function by inhibiting anti-gen driven proliferative responses of effector T cells anddecreasing the number of lymphocytes and granulocytes inbronchoalveolar fluid when transplanted [57]. These cellswere distinct from lung fibroblasts in terms of gene expres-sion, showing decreased expression of genes associatedwith inflammation, myofibroblast specification and extra-cellular matrix production. Unfortunately, as in other tis-sues, the heterogeneity of methods and markers used forthe definition and characterization of LR-MSCs makes itvery difficult to compare different studies and reach a con-sensus on their role at this time.Apoptosis of stromal cells has been proposed to beone of the main mechanisms leading to the resolution offibrosis during normal wound healing in many organs,and it is believed that in progressive fibrotic lesions,MSCs and their progeny escape its induction, leading toincreased matrix deposition. Proposed roles of macro-phages, T cells and the inflammatory microenvironmentin general in regulating the survival of LR-MSCs in air-way and interstitial pulmonary fibrosis are reviewed else-where [58].Alternative cellular sources for tissue-effectormyofibroblastsThe progression from regeneration to repair invariablyinvolves the development of fibrosis, defined as an ex-cessive deposition of extracellular matrix. The principalcell type known to be involved in this process is an acti-vated fibroblast derivative called a myo-fibroblast. Thetransition towards fibrosis was traditionally thought toinvolve expansion of stromal progenitors and subsequentdifferentiation into myo-fibroblasts, defined by increasedsynthesis of ECM proteins, such as fibrillar collagensand fibronectin as well as de-novo expression of alpha-smooth muscle actin. Although the importance of myofi-broblasts in the development of fibrosis is generallyaccepted, there continues to be a significant debatewhether alternative cellular sources, rather than differen-tiation from tissue-resident mesenchymal progenitors,exist for myofibroblasts.The notion that collagen-producing myofibroblastsarise solely from the proliferation and differentiation oftissue-resident cells began to be questioned in the mid-1990s when two alternative cellular sources were proposed:(1) epithelial cells undergoing epithelial-to-mesenchymaltransition (EMT) [59] and (2) circulating bone-marrowderived fibrocytes [5]. These concepts have importantimplications towards both the theoretical cellular processesunderlying the development of fibrosis, and also thedevelopment of novel therapeutics to abrogate theprocess. Despite a wealth of literature supporting boththeories, a growing number of recent studies employingmuch more rigorous lineage tracing analysis have cast asignificant degree of doubt on the notion that fibro-genic cells arise from sources outside of tissue-residentMSCs.Epithelial-to-mesenchymal transition (EMT)Long known to be involved in metazoan embryogenesis,recent studies provided evidence that epithelial mesen-chymal transition can also occur in adult tissues duringthe development of fibrosis as well as the progressionand metastasis of cancer. Although the prevalence, aswell as importance, of EMT in both embryogenesis andcancer is rarely disputed, a growing body of recent evi-dence has led many to reject the notion that EMT playsa role in solid organ regeneration and repair [60-62]. Re-cent use of more rigorous lineage tracing tools havestrongly called into question the ability of epithelial cellsto transition into collagen-producing mesenchymal cellsduring repair processes in numerous tissues, such as thekidneys [63-65], liver [66-68] and lungs [69]. There is agrowing consensus that although EMT can be achievedin vitro through transforming growth factor (TGF)β1treatment, this process does not make any significantcontribution in vivo during tissue repair. Additionally,research attributing EMT as an important source ofmyofibroblasts have widely used the marker FSP1 (alsoknown as S100A4) as a marker of epithelium-derivedfibroblasts, which has repeatedly been shown to notlabel collagen producing cells in some tissues [65] andto lack specificity by labeling other cells, such as mono-cytes, macrophages, neutrophils and granulocytes [70].Such critiques towards the field of EMT in tissue re-pair can also be applied to other processes, such asendothelial-to-mesenchymal transition (EndMT), whichhas used similarly questionable methods to demonstrateEndMT as an important source of tissue-effector myofi-broblasts [71]. Further, additional doubt can be cast onEMT and EndMT data due to recent reports which dem-onstrate that Cre drivers previously thought to exclu-sively label epithelial or endothelial lineages (for example,Tie2) do not possess the necessary specificity to concludethat progeny labeled by these markers are exclusivelyderived from the epithelium or endothelium [41].FibrocytesCirculating bone marrow derived mesenchymal progeni-tors, termed fibrocytes, have been proposed as a secondalternative source of collagen-producing myo-fibroblastsin situations of tissue repair [5]. First described in 1994[72], fibrocytes have classically been identified using acombination of hematopoietic markers CD34 and CD45,Pretheeban et al. Fibrogenesis & Tissue Repair 2012, 5:20 Page 6 of 12http://www.fibrogenesis.com/content/5/1/20as well as the mesenchymal markers vimentin and colla-gen 1, although numerous further markers have beenadded in recent years [73]. Although there continues tobe numerous studies published describing the role ofcirculating cells in the development of fibrosis, a numberof recent reports have begun to call into question thismodel. Central to arguments that oppose the role offibrocytes in fibrosis has been that much of the data sup-porting this model is based on phenotypical identifica-tion of fibroblasts of bone marrow derived origin, ratherthan characterization of the functional role these cellshave in the development of tissue fibrosis. Followingthis, more recent studies employing more sophisticatedtechniques, such as genetic polymorphisms of collagenproteins in sex mismatched transplant recipients [74], aswell as more specific collagen transgenics [75], have pro-vided compelling evidence that, in numerous types oftissue repair, collagen-producing myofibroblasts arisesolely from cells residing within the organ. Additionally,it should be noted that the same problematic reagentsemployed to identify the role of EMT in fibrosis, such asfibroblast markers of dubious specificity (for example,FSP1, vimentin) are also prevalent in a number of studiesexamining the role of fibrocytes [71].Signaling in MSCsGiven their relevance in tissue regeneration, MSCs mustmaintain fluid communication with their surroundings.Indeed, a variety of stimuli, including physical andchemical signals originating in both the niche and thesystemic environment, convey information to the MSCs.Integration of such signals can result in alteration of theotherwise quiescent state of MSCs, eliciting a sequenceof fate choices that may include proliferation, self-renewal, migration, differentiation and cell death. In theabsence of tissue damage and inflammation, systemicand metabolic cues can modulate the activity of stemcells under what can be regarded as homeostatic condi-tions [76]. Upon tissue damage, however, acute signalsbecome the leading cues directing MSC activity. Thecombination of systemic and acute stimuli eventuallydrives the fate choice of MSC-derived progenitors intolineages that will contribute to the regeneration of thetissue. Under pathological conditions, however, aberrantsignaling can lead to the development of ectopic celltypes that contribute to the degeneration of the damagedtissue. In addition to the better-characterized pathways,such as FGF, PDGF and EGF, current advances in thestudy of the TGFβ, BMP and Wnt signaling cascadeshave disclosed a critical role for these factors in theregulation of mesenchymal stem cell behavior duringtissue regeneration. The fact that the three pathwaysinteract closely, partly through shared intracellularcomponents, provides a number of interesting signalingcrossroads that will be worth exploring in furtherdepth. A summary of these signaling pathways andtheir effects is illustrated in Figure 3.TGFβ, a member of the TGFβ superfamily, constitutesone of the major regulators of mesenchymal fate choicein postnatal life [77]. TGFβ signaling supports the earlystages of chondroblastic and osteoblastic differentiation,while acting as an inhibitor of the advanced stages ofosteoblast differentiation [78]. TGFβ inhibits adipogenicdifferentiation [79] through a route that involves inter-action between the canonical complex SMAD3/SMAD4with the transcriptional regulator C/EBP [80].TGFβ signaling plays a pivotal role in both dermalhomeostasis and hair follicle regeneration, where TGFB2produced by the dermal papillae of the follicles driveshair follicle stem cells out of quiescence and activatesthem during the telogen-to-anagen transition [81].Timely TGFβ release is critical for the initial stages ofwound healing. Following damage, TGFβ1, -2 and −3 aresecreted by various cell types, including platelets, fibro-blasts, macrophages and keratinocytes. TGFβ signalingstimulates the temporary production of extracellularmatrix (ECM) by fibroblasts and attracts macrophagesthat will participate in the inflammatory response [82].Aberrant TGFβ signaling in the dermis, on the otherhand, elicits excessive ECM deposition, fibrosis and scarformation that can lead to the formation of skin keloids[82]. In addition to its effect on fibroblasts and macro-phages, TGFβ stimulates proliferation and sphere colonyformation in skin-derived precursors (SKPs) in vitro,without altering their multipotency [83]. Excessive TGFβproduction also correlates with skeletal muscle (SM)fibrosis [84], a characteristic feature of Duchenne mus-cular dystrophy [85]. Within SM, TGFβ targets mesen-chymal Lin-/α7-/Sca-1+/PDGFRa+ progenitor cells thatreside in the interstitial mesenchyme and can differenti-ate into collagen-producing fibroblasts [35]. Importantly,the same progenitor population can adopt the adipo-genic lineage upon SM degenerative damage, leading tointramuscular ectopic fat accumulation [19,20,31].The TGFβ family of signaling proteins is also import-ant in the maintenance and expansion of bone and car-tilage, largely through BMP proteins and TGFβ itself[76]. TGFβ promotes the proliferation, early differenti-ation and lineage commitment of bone progenitorsthrough Smad2/3 and TAK1-MKK-p38 signaling [78].Members of the BMP: BMP-2, 4, 5, 6 and 7 constituteosteogenic inducers. In particular, BMP-2 expression issufficient for full osteogenic commitment, and loss ofBMP-2 leads to impaired osteogenesis [86]. BMP-2 sig-nals through type -I and -II BMP receptors and throughthe ALK2 receptor, leading to the activation of theSmad1/5/8 canonical pathway [87,88]. Following TGFβand BMP induction, Smad and MAPK signals convergePretheeban et al. Fibrogenesis & Tissue Repair 2012, 5:20 Page 7 of 12http://www.fibrogenesis.com/content/5/1/20to regulate the activity of Runx2, a master transcrip-tional regulator that commands the expression of theosteogenic gene program, via Dlx5 [77]. In addition,Dlx5 also activates Osterix, a regulator of osteoblastmaturation, independently of Runx2 activation [89].Importantly, both the TGFβ and the BMP pathwaysconnect with other signals that participate in bone for-mation. Components of the TGFβ signaling pathwayinteract with components of the pituitary hormone(PTH), Wnt and fibroblast growth factor (FGF) signalingpathways [90]. The BMP pathway, on the other hand,cross-talks with Notch, FGF and Wnt signaling [90].Aberrant BMP signaling has been linked to heterotopicossification, a pathological condition characterized bybone formation in skeletal muscle and soft tissues [40].Mutations in the regulatory domain of the Alk2 receptorleading to hyper activation of the BMP signaling path-way have been shown to mimic the pathophysiology offibrodysplasia ossificans progressive (FOP), an extremeform of heterotopic ossification [91]. Recent advances inthe identification of the cellular substrate of FOP indi-cate that a muscle-resident Lin-/Sca-1+/PDGFRa+/Tie2+mesenchymal cell population can also adopt the osteo-genic lineage upon induction with BMP2 [41]. Consist-ent with the previously discussed role of Lin-/Sca-1+/PDGFRa+ cells in SM fibro-fatty degeneration, theLin-/Sca-1+/PDGFRa+/Tie2+ cells also generated ectopicadipocytes in the lesions induced by BMP2 injection [41].The Wnt family comprises secreted cysteine-rich gly-copeptides that act in a paracrine and autocrine mannerWnt10b TGFβBMPsBMPRIBMPRIITGFβRIRYKTGFβRIISmad 2, 3Smad 2, 3Smad 2, 3Smad 1, 5, 8Smad 1, 5, 8Smad 1, 5, 8Smad 4Smad 4Smad 4OsteogenesisFibrogenesisAdipogenesisWnt5bFrizzledLRPAxin GSK3TAK1MKK 3, 6p38 α, βTAK1PPPPPPPβ-cateninβ-cateninTCFCBPFigure 3 Signaling pathways driving mesenchymal stem cells to differentiate into lineages found in reparative disorders. While Wnt10brepresses adipogenesis through the activity of B-catenin/TCF/Lef transcriptional complexes, activation of the non-canonical Wnt pathway byWnt5b leads to repression of TCF/β-catenin transcriptional activity and yields the opposite results. Non-canonical TGFβ signaling participates inbone formation through activation of the osteogenesis regulator Runx2. On the other hand, canonical TGFβ signaling plays a central role in theregulation of the fibrogenic gene program. The BMP signaling pathway drives osteogenesis through SMADs 1, 5, 8 and shares the SMAD4component with the TGFβ pathway.Pretheeban et al. Fibrogenesis & Tissue Repair 2012, 5:20 Page 8 of 12http://www.fibrogenesis.com/content/5/1/20through a so-called canonical B-catenin-dependent and/ora non-canonical B-catenin-independent pathway. MSCshave been reported to express several Wnt ligands, includ-ing Wnt2, Wnt4, Wnt5a, Wnt11 and Wnt16, along withWnt receptors of the Frizzled (FZD) family FZD2, 3, 4, 5and 6, and co-receptors including LRP5 and 6. While thecontribution of B-catenin-independent signaling on MSCactivity is poorly understood, B-catenin-dependent signal-ing has been shown to play an important role in adipo-genic and osteogenic differentiation of MSCs. Binding ofWnt to the FZD/LRP receptor complex induces the dis-sociation of the Axin/APC/GSK3B complex which, in theabsence of Wnt signaling, phosphorylates B-cateninleading to its ubiquitination and degradation. Uponstabilization, B-catenin translocates into the nucleus,where it interacts with transcription factors of thelymphoid enhancer-binding factor/T-cell-specific factor(LEF/TCF) to induce the transcription of Wnt-regulatedgenes. Wnt molecules participate in adipogenic differenti-ation via the canonical B-catenin pathway. Wnt10b main-tains preadipocytes undifferentiated by blocking theactivity of the pro-adipogenic factors C/EBPα and PPARγ[92,93]. Indeed, transgenic mice overexpressing Wnt10bunder the FABP4 promoter possess less adipose tissue inregular diet conditions and are resistant to diet-inducedobesity. Those data were confirmed independently byoverexpression of a dominant-negative form of TCF4 thatfacilitated adipogenic differentiation. Wnt5 also blocksPPARγ function, through a mechanism that involvesH3K9 methylation [94]. In contrast to their inhibitoryeffect on adipogenesis, Wnt molecules induce osteogenicdifferentiation of MSCs. Osteogenic differentiation ofMSCs - via a non-canonical pathway - with concomitantinhibition of adipogenic mechanisms has been shown tooccur in MSCs [95,96]. The dual role of Wnt5 has alsobeen shown in vivo, in the above-mentioned FABP4-WNT10B transgenic mice, in which the reduction in fattissue is accompanied by an increase in bone mass, andreduced bone loss [97]. Altogether, a pivotal role for theWnt family can be proposed by which these moleculesregulate the balance between adipogenic vs. osteogeniclineage in MSCs.ConclusionsReparative disorders are commonly accompanied withtissue injuries and subsequent repair processes. Stemcells are extremely important for tissue repair either bydifferentiating into new cells to replace damaged tissue(TSCs) or to aid in the regenerative or reparative process(MSCs). During the past decade, employment of variousisolation and lineage-tracing methods both in vivo andin vitro has led to the identification of several types ofadult tissue resident stem cells in distinct organs, and ofa phenotypically homogeneous population of stromalprogenitors present in all tissues analyzed and likely tobe the in vivo equivalent of the ill-defined but oftenmentioned “mesenchymal stem cell”. However, the drawback in many studies has been the presence of functionalheterogeneity within stem cell populations, which hin-ders the generalized characterization or comparison ofthese cells across species and tissues to use in thera-peutic settings. Overcoming this obstacle will likely re-quire high throughput single cell analysis techniquesthat are just starting to be available. Apart from theirwell-established role in regeneration, TSCs may alsocontribute to fibrosis, fatty degeneration or heterotopicossification. To what extent this happens, however, is asyet unknown, and overwhelming evidence implicatesMSCs as the main culprits for most reparative disorders.In addition, recent findings fundamentally challenge thehypothesis that MSCs also derive from EMT or EndMT,and the existence of circulating fibrocytes, suggestingthat local progenitors are the main cell type involved inrepair. Although MSCs’ participation in reparative disor-ders is proven, the molecular mechanisms by which theycontrol the reparative process and regulate other celltypes involved is critical for therapeutic intervention andin turn alter the fate choices of MSCs during repair.Promisingly, tissue resident MSCs have the potential tobe included in cell-based therapies to treat reparativedisorders as alternative autologous cell sources. More-over, TGFβ, BMP and Wnt signaling cascades are con-sidered as key communication partners with otherknown signaling molecules in the regulation of MSCsand, therefore, viewed as potential therapeutic targets.To fruitfully deploy modulators of these pathways, how-ever, the complexity of interaction of MSCs both atcellular and molecular levels need to be furtherelucidated.AbbreviationsCFU-Fs: Colony forming unit – fibroblasts; ECM: Extracellular matrix;EMT: Epithelial-mesenchymal transition; EndMT: Endothelial-mesenchymaltransition; FAPs: Fibro-adipogenic progenitors; FGF: Fibroblast growth factor;FZD: Frizzled; LEF/TCF: Lymphoid enhancer-binding factor/T-cell-specificfactor; LR-MSCs: Lung derived/resident MSCs; MDSPCs: Muscle derived stem/progenitor cells; MSCs: Mesenchymal stromal cells; SKPs: Skin-derivedprecursors; SMN: Survival of motor neuron; TGF: Transforming growth factor;TSCs: Tissue-specific resident stem cells.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsTP, DRL, BP and RHZ surveyed the literature and were involved in draftingthe manuscript. 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Fibrogenesis & Tissue Repair 2012 5:20.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitPretheeban et al. Fibrogenesis & Tissue Repair 2012, 5:20 Page 12 of 12http://www.fibrogenesis.com/content/5/1/20

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