Stem cells for skeletal muscle regeneration: therapeutic potential and roadblocks FABRIZIO RINALDI, and RITA C. R. PERLINGEIRO MINNEAPOLIS, MINN
Conditions involving muscle wasting, such as muscular dystrophies, cachexia, and sarcopenia, would benefit from approaches that promote skeletal muscle regeneration. Stem cells are particularly attractive because they are able to differentiate into specialized cell types while retaining the ability to self-renew and, thus, provide a long-term response. This review will discuss recent advancements on different types of stem cells that have been attributed to be endowed with muscle regenerative potential. We will discuss the nature of these cells and their advantages and disadvantages in regards to therapy for muscular dystrophies. (Translational Research 2014;163:409–417) Abbreviations: DMD ¼ Duchenne muscular dystrophy; ES cells ¼ embryonic stem cells; iPS cells ¼ induced pluripotent stem cells; MD ¼ muscular dystrophy; MDSCs ¼ muscle-derived stem cells; MyoD ¼ myogenic differentiation antigen; Pax3 ¼ paired box homeodomain 3; Pax7 ¼ paired box homeodomain 7
M
uscular dystrophies (MDs) comprise more than 30 neuromuscular disorders of inherited origin.1 A common feature of this clinically and genetically heterogeneous group of disorders is progressive muscle weakness in particular subsets of degenerating skeletal muscles, which leads to atrophy, and frequently the confinement of affected patients to a wheelchair. The most common, Duchenne muscular dystrophy (DMD), affects one out of 5000 male live births, and is caused by mutations in the dystrophin gene that result in biochemical defects of the dystrophin-glycoprotein complex in skeletal muscle and other tissues.2,3 Affected patients lose mobility by
From the Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis, Minn. Submitted for publication September 16, 2013; revision submitted November 1, 2013; accepted for publication November 7, 2013. Reprint requests: Rita C.R. Perlingeiro, PhD, Lillehei Heart Institute, University of Minnesota, 4-128 CCRB, 2231 6th St. SE, Minneapolis, MN 55455; e-mail:
[email protected]. 1931-5244/$ - see front matter Ó 2014 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.trsl.2013.11.006
their teenager years with eventual death because of respiratory and/or cardiac failure. Loss of skeletal muscle mass is also observed in the aging population, a process known as sarcopenia, and as a secondary effect in some cancer patients, known as cachexia. These conditions can also cause severe debilitating weakness and metabolic dysfunction.4-7 Skeletal muscle comprises about 40% of the human body mass, and it is well recognized for its robust capacity for regeneration. Seminal observations in this regard were first described in 1953 by Russian investigator A.N. Studitsky, who chopped a muscle biopsy into 1-mm3 pieces and observed remarkable new muscle formation following reimplantation of this minced muscle tissue back into the muscle bed.8 This rudimentary model was proven to be very useful to understand the initial principles of skeletal muscle regeneration. Subsequently, Carlson and Gutmann9 repeated these experiments in rats and demonstrated that the new fibers were functionally and morphologically similar to those present in normal muscle. Several years later, this model was used to investigate the impact of age on this regenerative process. Whereas young and aged minced muscle tissue regenerated well in young hosts, this was not the case in aged hosts,10,11 indicating for the first time that 409
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the environment plays an important role in skeletal muscle regeneration. Several recent reports have corroborated this observation.12-15 Based on the premise of this incredible regenerative capacity, pioneering studies initiated in the late 1980s16 and extended into the 1990s17-19 began to explore cell-based therapies to promote muscle regeneration as a potential treatment for MDs. Initially, most of these studies focused on the transplantation of adult myoblasts aiming to regenerate skeletal muscle by the fusion of those cells (donor myoblasts) with recipient’s cells to form new or hybrid fibers. Adult myoblasts were isolated from muscle biopsies and expanded ex vivo before transplantation.16-18 Despite the encouraging findings obtained using the dystrophindeficient mdx mouse model, clinical trials performed in a cohort of DMD patients were disheartening due to poor myoblast transfer efficacy and failure to improve strength in treated muscles.3,20,21 Major factors underlining this poor outcome included low ability of myoblasts to migrate beyond the injection site22,23 and poor survival of injected cells.24,25 Several research groups have been working toward the goal of overcoming these issues as well as the immune response observed in the recipient following myoblast transfer.26-29 As an alternative to poorly engrafting myoblasts, much recent interest has developed around the idea of therapy with stem cells. These cells have the ability to self-renew and to differentiate into specialized cell types, and can be primarily classified as adult and pluripotent stem cells, which differ significantly in regard to their differentiation potential and in vitro expansion capability. Adult stem cells are tissuespecific and have limited capacity to be expanded ex vivo whereas pluripotent stem cells have the ability to differentiate into any cell type of the body while possessing unlimited in vitro self-renewal. Below we review the literature on some of the most studied stem cell populations that have been ascribed with in vivo muscle regenerative potential, pointing out their advantages as well as caveats. ADULT STEM CELLS Satellite cells. Studies in the last decade have clearly proven that the regenerative ability of adult skeletal muscle is due to the satellite cell, a quiescent stem cell population of muscle precursors located between the basal lamina and sarcolemma of each myofiber.30-32 The satellite cell was first described by Mauro in 1961 using electron microscopy,33 and later by Bishoff 34 in 1986 using phase-contrast microscopy on single myofiber explants. Upon injury, satellite cells become
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activated, giving rise to proliferating myoblasts, which then fuse to existing muscle fibers or to other myoblasts to form new myofibers to repair muscle damage.35-39 Meanwhile, a small subset of satellite cells does not undergo differentiation but retains the ability to return to a quiescent state and thus preserve the satellite cell pool.4,30,40,41 In addition to their typical localization, a hallmark of these cells is the expression of Pax7, a paired box homeodomaincontaining transcription factor32,42 necessary for the maintenance of the muscle stem cell compartment in adult mice32,42-44 as well proliferation following injury45 and, consequently, being indispensable for adult skeletal muscle regeneration.46 There is evidence for heterogeneity within the satellite cell compartment, with a subset of satellite cells having greater potential to engraft the satellite cell compartment.45,47,48 It took about 50 years from their initial identification in the early 1960s for pure preparations of mouse satellite cells to be isolated and tested for their regenerative potential.30,31 One group took the approach of transplanting single muscle fibers, which demonstrated that each myofiber, containing 7 or fewer satellite cells, could generate over 100 new myofibers in engrafted muscles.30 The other approach made use of a transgenic reporter mouse for Pax3, a paralog of Pax7, which allowed for the direct isolation of Pax31 (green fluorescent protein1) muscle satellite cells by flow cytometry.31 Cells isolated from adult skeletal muscles displayed homogenous expression of Pax7, and contributed to both fiber repair and to the muscle satellite cell compartment following their transplantation into dystrophic mice.31 Subsequently Sacco et al demonstrated that intramuscular transplantation of a single luciferase-expressing muscle stem cell, isolated from Myf5 reporter mice, resulted in extensive proliferation and contribution to muscle fibers. In addition, these authors showed that Pax7(1)luciferase(1) mononuclear cells could be readily re-isolated, providing evidence for the self-renewal of this cell population.49 Satellite cells have also been characterized phenotypically by the expression of several surface markers, such as M-cadherin,50 CD34,51 syndecan-3/4,52 a7b1integrin,53,54 and the chemokine receptor CXCR4,55 among others.56-59 The first report making use of surface markers to isolate muscle precursor cells was published in 2004, in which the authors used a combination of negative and positive selection to discern muscle activity among different cell fractions.60 In vitro and in vivo myogenic potential was found within the CD45-Sca-1-Mac-1-CXCR41b1integrin1CD341.60,61 In 2009, Tanaka et al62 documented that the Sca-11/ABCG21/Syndecan-41 cell
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subpopulation expresses Pax7 and participates in muscle regeneration in vivo, as showed by myofiber and satellite cell engraftment. The generation of reporter mouse models for Pax763,64 has enabled better characterization of the satellite cell compartment, not only in terms of their regulation but also functionality.47,65-67 In a recent report, Arpke et al68 have confirmed the potency of satellite cells since the transplantation of as few as 900 Pax71 satellite cells resulted in clearly measurable improvement of muscle function in dystrophic mice. In summary, a lot has been learned about satellite cells in the last decade, and these promising findings confirm that satellite cells represent a potent cell source for skeletal muscle regeneration. Challenges to be circumvented are the optimization of protocols to isolate human satellite cells because the surface markers identified in the mouse are not necessarily applicable to the human counterparts. To date, investigators have used antibodies to neural cell adhesion molecule (N-CAM) to identify satellite cells in human tissues.69-72 Perhaps the greatest challenge in applying these cells in the clinical setting is to obtain enough cells for transplantation since activation and in vitro expansion diminishes their engraftment ability.31 Strategies that allow for the in vitro expansion of satellite cells would be desirable. Muscle-derived stem cells. A population known as muscle derived stem cells (MDSCs) has been identified in the mouse muscle interstitial space.73 These cells, isolated based on their adhesion characteristics using the preplating method, can be expanded in vitro for up to 30 passages while maintaining myogenic potential.24,74 Because satellite cells are nonadherent, it is likely that MDSC preparations include satellite cells. Upon transplantation into dystrophic mice, MDSCs contribute to muscle regeneration following their local24,74 or systemic injection,75 although there is currently no evidence that these preparations can improve function in treated muscles.76 Recently, 2 studies have documented the isolation of human MDSCs based on their delayed adherence to collagencoated plates.77,78 These cells were able to differentiate in vitro but after injection into the gastrocnemius muscles of mdx/SCID mice, engraftment levels were not robust.77 Mesoangioblasts/pericytes. Mesoangioblasts, first identified as an embryonic population of vesselassociated stem cells isolated in the dorsal aorta,79 were reported to have the ability to differentiate into most mesodermal cell types, including skeletal muscle.80 Mesoangioblasts have been shown to express some of the markers commonly associated with satellite cells, such as M-cadherin, CD34, and
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Myf5, however, distinctively from satellite cells, these cells can be grown extensively in culture.79 Intraarterial transplantation studies using mouse and dog models of MD demonstrated that these cells engraft substantially, restoring normal muscle morphology and improving muscle function.81,82 With these encouraging results, the same authors evolved their studies to human muscle samples and came to the conclusion that pericytes are the human equivalent of the mouse mesoangioblasts.83 These cells are found in the muscle microvasculature, are proliferative, display muscle regenerative potential, and express pericyte markers (ie, NG2 proteoglycan and alkaline phosphatase) but not endothelial markers.83 Such as their mouse counterparts, pericytes have been shown to generate new myofibers as well as to assume satellite cell position and express Pax7 after intraarterial injection into immunodeficient mdx mice.84 Genetic correction has been successfully applied to mesoangioblasts isolated from dystrophic donors.81,85 Based on these encouraging results, there is an ongoing phase I/II clinical trial focused on the use of allogeneic human leukocyte antigen-identical mesoangioblasts to treat pediatric patients affected by DMD (EudraCT no. 2011-000176-33). A major caveat when moving to larger numbers of patient samples is the variability in the in vitro scalability of pericytes.86 As one would expect, they seem to have a finite lifespan in culture, which is inversely correlated with age. Thus, obtaining enough cell material to systemically treat a patient may be challenging. PLURIPOTENT STEM CELLS Embryonic stem cells. Embryonic stem (ES) cells, first isolated from the inner cell mass of blastocyst-stage preimplantation mouse embryos,87,88 are pluripotent and, thus, endowed with the ability to differentiate into all 3 germ layers, mesoderm, ectoderm, and endoderm, and importantly, are able to be maintained indefinitely in the undifferentiated stage in the presence of specific culture conditions. Almost 20 years later, human ES cells were isolated from fertilized human embryos,89 providing the rationale for investigators to pursue differentiation methods to study lineage-specific cell populations and to envision a potential therapeutic application for these cells. While several lineages are easily recapitulated during the in vitro differentiation of ES cells, such as blood,90-93 cardiac muscle,94 and endothelial,95 skeletal muscle has proven to be more difficult. Although early gene expression studies of embryoid bodies and their outgrowths suggested a temporal expression of myogenic regulatory factors, detection of differentiated
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myogenic cells was elusive.96 Similarly, early transplantation studies of mouse and human differentiating ES cells were not highly promising in terms of the myogenic potential of isolated cells.97,98 In the first study, mouse EBs had to be cocultured with primary muscle precursor cells for 4 days prior to transplantation in dystrophic mice.97 In the second study, the authors transplanted human ES cells taken through a mesenchymal differentiation protocol into immunodeficient mice and detected a few myogenic cells as shown by staining for human nuclear antigen and laminin.98 In this multistep differentiation protocol, gene expression of Pax7 and myogenic differentiation antigen (MyoD) was not observed until 30 days in culture or longer. In 2008, Darabi et al99 proposed that the poor skeletal muscle formation observed in ES cell cultures was due to the fact that key embryonic structures (ie, somite, neural tube, notochord) and thus inductive signals necessary for proper patterning of paraxial mesoderm and subsequent activation of the myogenic program are not well recapitulated during EB differentiation. By using transient expression of Pax399 or Pax7100 during early mesoderm development, these authors showed that it is possible to bypass inefficient mesoderm patterning. This approach allowed for the in vitro generation of large quantities of early embryonic skeletal myogenic progenitors, whose transplantation into dystrophic mice resulted in high levels of myofiber and satellite cell engraftment that was accompanied by improvement in muscle force generation.99-102 Following these encouraging results, attempts have been made toward generating paraxial mesoderm and subsequent skeletal muscle without genetic modification.103,104 It has been demonstrated that serum-free ES-derived monolayers cultured with bone morphogenetic protein 4 for a short period and then incubated with lithium chloride promoted the differentiation of myogenic progenitor cells from paraxial mesoderm, although transplantation potential has not yet been documented.104 Another approach relied on the purification of satellite-like cells from differentiating mouse ES cells using a SM/C-2.6 antibody,105 which had been previously identified in quiescent satellite cells.106 The engraftment ability of SM/C-2.61 cells purified from differentiating mouse ES cells was demonstrated in mdx mice using serial transplantations.105 Despite the potential application of the findings discussed above, major limitations with ES cells are their potential rejection due to immunologic mismatch and the ethical concerns associated with their utilization in the clinics. These particular hurdles have been circumvented with the discovery of reprogramming somatic cells to an induced pluripotent state by the introduction
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of Oct4, Klf4, Sox2, and c-Myc,107-111 as detailed below. Induced pluripotent stem cells. Induced pluripotent stem (iPS) cells have been shown by several investigators to behave very similarly to ES cells in terms of pluripotency,107-116 and the generation of patientspecific iPS cell lines that could be used for autologous transplantation following appropriate in vitro differentiation has attracted great interest. A mandatory requirement for the potential therapeutic application of iPS cells is the generation of abundant tissue-specific, tumor-free, cell populations that are able to integrate and properly function in the host following transplantation. Strategies used to generate skeletal muscle from mouse ES cells were then validated with mouse iPS cells. Mizuno et al117 used the SM/C-2.6 antibody to purify iPS-derived satellite-like cells, while Darabi et al118 applied controlled expression of Pax7 during EB differentiation of mouse iPS cells, along with purification for PDGFaR1Flk-1- paraxial mesoderm, as shown for mouse ES cells.99 The generation of functional human skeletal myogenic progenitors from pluripotent cells has recently been accomplished using the Pax7 induction protocol.119 In this study, the authors demonstrated the feasibility of generating large quantities of human ESand iPS-derived early skeletal myogenic progenitors, which had the ability to promote robust regeneration and to improve the force generation of engrafted muscles upon transplantation into immunodeficient dystrophic mice. These cells were also shown to contribute to the satellite cell pool, and accordingly durable engraftment was observed in a long-term cohort of treated mice (46 weeks) that were devoid of teratoma or abnormal cell growth.119 MyoD and Myf5 have also been used to pattern mesoderm from human pluripotent cells.120,121 In the case of MyoD, modified cells participated in muscle regeneration by fusing efficiently with existing muscle fibers following their transplantation into Rag/mdx mice.120 Also in 2012, another study described a stepwise culture method for the expansion of mesenchymal cells from human EBs, which differentiated into mature myotubes in vitro, a process that took 64 days in culture. Transplantation of these myogenic mesenchymal cells, isolated at day 49, into pre-irradiated and cardiotoxin-injured muscles of immunodeficient mice resulted in engraftment as shown by the presence of human nuclei.122 To date the SM/C-2.6 antibody used to purify myogenic progenitors from differentiating mouse ES and iPS cells105,117 has not been shown to recognize the human counterparts. Potential for the genetic correction of disease-specific iPS cells. The encouraging results discussed above
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Fig 1. Schematic representation of the stem populations described in this review.
bring about the possibility of generating MD patientspecific iPS cells that could be used for autologous transplantation, following proper genetic correction. Proof-of-principle studies in this direction were recently reported by Filareto et al123 using mouse dystrophic iPS cells. In this study, the authors generated iPS cells from fibroblasts obtained from dystrophin/utrophin double knockout mice, which display a severe phenotype that much resembles the human DMD pathology.124,125 Dystrophic iPS cells were corrected by insertion of the micro-utrophin (mUTRN) gene, which has been shown to ameliorate the dystrophic phenotype,126-129 using the sleeping beauty transposon system. Transplantation of mUTRNcorrected iPS-derived skeletal myogenic progenitors, generated using the Pax3 induction approach,99 into double knockout mice resulted in substantial engraftment, as evidenced by the presence of donorderived utrophin1 myofibers and satellite cells, as well as improved muscle strength.123 As discussed above, although mesoangioblasts/ pericytes have reported in vitro expansion potential, obtaining enough cell material from adult patients has proven to be more challenging. Tedesco et al130 have
recently used a protocol to derive mesoangioblast/ mesenchymal-like cells from iPSCs derived from healthy individuals and from patients affected by limb-girdle 2d type MD. Mesoangioblast/mesenchymal-like cells, generated from iPS cells, were expanded, corrected with a lentiviral vector encoding the human a-sarcoglycan gene (SGCA), and subsequently differentiated into myogenic cells following MyoD modification. Transplantation of genetically corrected cells resulted in engraftment and functional amelioration of the dystrophic phenotype upon their intramuscular or intra-arterial injection into a-sarcoglycan-null immunodeficient mice.130 CONCLUSIONS
In this review, we covered stem cell types (Fig. 1) that have been most studied within the last decade in terms of regenerative capacity for the potential treatment of neuromuscular disorders. As pointed out, each cell type presents its own advantages and limitations. Currently, bona-fide satellite cells cannot be used until approaches are developed to expand these cells in vitro. This may be accomplished in the near future, as we gain more mechanistic insight on the signaling
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pathways that regulate satellite cell self-renewal. Ongoing clinical trials with mesoangioblasts/pericytes have indicated no side effects for these cell preparations so far, although data on efficacy have not been reported yet. As discussed above, in vitro expansion of these cells may be an issue for older patients. iPS cell technology provides an exciting opportunity for cell-based therapies. However, several safety concerns need to be overcome before they can be considered for clinical applications,131,132 including (1) the development of an efficient integration-free method for their generation as well as for the subsequent derivation of skeletal myogenic progenitors, (2) safe gene correction strategies, and (3) purification of target cells to avoid the presence of tumor-forming undifferentiated ES and iPS cells to eliminate the risk of the transplanted cells to generate tumors in the host. Another important aspect to keep in mind in terms of stem cell transplantation for neuromuscular disorders is the method for delivering the cells. Because the skeletal muscle is the largest organ of the human body, and in most conditions, multiple muscle groups are affected, local intramuscular cell injection is not a feasible strategy. Thus, it is critical that selected stem cell preparations have efficient and selective skeletal muscle homing ability following systemic delivery. ACKNOWLEDGMENTS
This project was supported by National Institutes of Health grants R01 AR055299 and RC1AR058118 as well as funding from the Muscular Dystrophy Association (#238127). All authors have read the journal’s policy on disclosure of potential conflicts of interest. The authors declare no potential conflicts of interest. REFERENCES
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