Neuropathology and Applied Neurobiology (2015), 41, 270–287

doi: 10.1111/nan.12198

Invited review: Stem cells and muscle diseases: advances in cell therapy strategies E. Negroni, T. Gidaro, A. Bigot, G. S. Butler-Browne, V. Mouly and C. Trollet Institut de Myologie, CNRS FRE3617, UPMC Univ Paris 06, UM76, INSERM U974, Sorbonne Universités, 47 bd de l’Hôpital, Paris 75013, France

E. Negroni, T. Gidaro, A. Bigot, G. S. Butler-Browne, V. Mouly and C. Trollet (2015) Neuropathology and Applied Neurobiology 41, 270–287 Stem cells and muscle diseases: advances in cell therapy strategies Despite considerable progress to increase our understanding of muscle genetics, pathophysiology, molecular and cellular partners involved in muscular dystrophies and muscle ageing, there is still a crucial need for effective treatments to counteract muscle degeneration and muscle wasting in such conditions. This review focuses on cellbased therapy for muscle diseases. We give an overview of the different parameters that have to be taken into account in such a therapeutic strategy, including the influence of muscle ageing, cell proliferation and migra-

tion capacities, as well as the translation of preclinical results in rodent into human clinical approaches. We describe recent advances in different types of human myogenic stem cells, with a particular emphasis on myoblasts but also on other candidate cells described so far [CD133+ cells, aldehyde dehydrogenase-positive cells (ALDH+), muscle-derived stem cells (MuStem), embryonic stem cells (ES) and induced pluripotent stem cells (iPS)]. Finally, we provide an update of ongoing clinical trials using cell therapy strategies.

Keywords: cell therapy, muscle ageing, muscular dystrophy, myoblast, satellite cells, transplantation

Muscle diseases and therapies

Skeletal muscle Skeletal muscles constitute 40–50% of the body mass in adult human and encompass a broad range of different muscles. Skeletal muscle is a highly specialized tissue required for many physiological processes including locomotion, maintenance of posture, as well as metabolic activity. Skeletal muscle is able to tolerate chronic mechanical and physiological stresses throughout life to maintain proper contractile function. Skeletal muscle is composed of contractile units called muscle fibres bundled together and attached to the skeleton by tendons. Muscle Correspondence: Capucine Trollet, Myology Research Center, UMRS 974 UPMC – INSERM – FRE 3617 CNRS – AIM, 47, bld de l’hôpital – G.H. Pitié-Salpétrière – Bâtiment Babinski, 75651 Paris cedex 13, France. Tel: +33 01 4216 5715; Fax: +33 01 4216 5700; E-mail: [email protected]

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fibres are post-mitotic multinucleated cells, surrounded by a specialized plasma membrane – the sarcolemma – and by a layer of extracellular matrix known as the basement membrane, which is composed of both an internal basal lamina and an external reticular lamina. The basal lamina associates closely with the sarcolemma providing a protective niche in which muscle precursors – called satellite cells (SC) [1] – reside. Muscle SC have a remarkable capacity to self renew and are also responsible for skeletal muscle growth and repair. Repair is crucial in conditions of muscle wasting including muscular dystrophies and muscle ageing. SC represent the adult stem cell of skeletal muscle [2]. Normally quiescent, in response to muscle damage, SC are able to activate, proliferate and fuse to repair the gap created in a myofibre by segmental necrosis or form new multinucleated myofibres. Identified in early studies on the basis of their position, beneath the basal lamina, by electron microscopy, SC are today identified by numerous © 2014 British Neuropathological Society

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Table 1. Muscle satellite cell markers Satellite cell state

Transcription factors Pax7 Myf5 MyoD Cell membrane proteins M-cadherin Caveolin 1 Syndecan 3 and 4 c-met CD34 CD56 CXCR4 a7integrin/B1integrin Cytoskeleton proteins Desmin Nestin

Detected in

Quiescent

Activation

Proliferation

Mouse

Human

+ − −

+ + +

+ + +

✓ ✓ ✓

✓ ? ✓

+ + + + + + + +

+ + + + + + ? +

+ + + + − + ? ?

✓ ✓ ✓ ✓ ✓ NA ✓ ✓

✓ ? ? ? ? ✓ ? ?

− +

+ +

+ ?

✓ ✓

✓ ?

NA, non applicable.

protein markers [3], allowing their identification in different cell state (quiescence, activation and proliferation) in mice and in humans (Table 1).

Satellite cells and muscle ageing Ageing results from the lifelong accumulation of subtle damages, caused by an exposure to biological and biochemical stresses. One of the detrimental hallmarks of muscle ageing is the decreased regenerative capacity after trauma or surgery, thus leading to longer immobilization, loss of muscle mass, increased sarcopenia and frailty. Age-related muscle decline can be exacerbated in patients with late onset degenerative disorders [4]. It is therefore essential to have a better understanding of the mechanisms of SC ageing to adapt therapeutic strategies, especially for late onset muscle diseases. The regenerative capacity of skeletal muscle is dependent on SC number and function, that is the ability of SC to activate, proliferate and differentiate. In mouse the decline in muscle regenerative capacity has been partly attributed to extrinsic environmental influences and diverse intrinsic potential of the SC themselves [5]. When old murine SC are exposed to a young environment or to growth factors, their capacity to proliferate and differentiate is partly restored [6–9], suggesting an influence of the muscle environment on the myogenic potency of old SC. In favour of a role for the environment, a recent © 2014 British Neuropathological Society

study underlines the function of oxytocin, a circulating hormone, which declines with age. A systemic administration of oxytocin improves muscle regeneration by enhancing activation – proliferation of aged SC [10]. One of the factors suggested to play a role in the decrease of regenerative capacity with age is the decrease in the number of resident stem cells. In humans, the number of SC decreases with age, from 4% to 5% in young adult subjects (∼20–30 years old) to 1% or less in old subjects (∼60–80 years old) [11,12]. SC depletion could be explained by a decrease in the ability of SC to return to quiescence to restore the pool of stem cells during the regeneration process or by an inability of SC to retain a quiescent state under homeostatic conditions. For example, an increase of fibroblast growth factor 2 (FGF2) from aged muscle fibres under homeostatic conditions leads to the loss of quiescence and depletion of SC [13], underlining the important role of the microenvironment in the regulation of SC function and maintenance of the stem cell pool. In a recent study, SousaVictor et al. demonstrated that the regenerative capacity of SC in geriatric mice cannot be restored after transplantation in young mice, as in geriatric mice, SC loose reversible quiescence and switch into a presenescence state. After injury, geriatric SC are therefore not able to participate to muscle regeneration and enter into a senescence state caused by derepression of the cell cycle inhibitor p16 [14]. A high level of p16 and senescent NAN 2015; 41: 270–287

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markers associated with the elevated activity of both the p38α and p38β pathways were also described in aged mouse SC [15]. In addition, comparison between quiescent SC from young and old mice show that epigenetic changes accumulate with ageing and are linked to functional defects in aged SC [16]. All these results indicate that during homeostasis in the mouse, both the local environment as well as the micro-environment – that is niche of SC – play essential roles in SC regulation. This suggests that during murine regeneration the intrinsic defect present in the aged SC cannot be entirely corrected by a permissive environment. Several studies are working on improving the regeneration capacity of aged SC in mouse models, as an example, a rejuvenation of aged mouse SC was made by acting on p38α and p38β pathways in association with culture of SC on soft hydrogel substrates to develop autologous muscle cell transplantation [15]. These are important considerations that have to be kept in mind for the development of efficient cell therapy procedures. However, the situation differs in humans where very little differences were observed in proliferative capacity and in initial telomere length in SC isolated from adults with various ages, including elderly subjects [17]. This suggests that cell therapy can be a therapeutic option even in elderly subjects, as long as the SC have not exhausted their proliferative potential due to either a dystrophic process or extensive expansion in vitro and are still able to participate in the host’s regeneration, taking into account the difference in scale from mouse to human [18]. Although more work on human SC ageing needs to be developed in the future, one can already consider that whenever possible, e.g. in muscular dystrophies, the earlier the therapy starts, the highest chance of success it will have.

Muscular dystrophies Muscle tissue has more than 80 associated monogenic pathologies. Among them, muscular dystrophies (MDs) are a heterogeneous group of muscle diseases clinically characterized by progressive muscle wasting and weakness, with a wide clinical presentation and severity [19]. MDs have been classified according to age of onset (perinatal or adults), mode of inheritance (X-linked, autosomal recessive or dominant) and the specific muscle groups initially affected (limb-girdle, proximal, distal and facial muscles). Over the past years, more than 30 genetically distinct types of MDs have been identified [20,21] (see © 2014 British Neuropathological Society

http://www.musclegenetable.fr/ for an updated table of genetic neuromuscular disorders). Mutated genes involved in the development of MD encode a broad range of proteins located in the extracellular matrix (collagen and laminin), at the plasma membrane (dystrophin, dystroglycan, sarcoglycan, integrins, dysferlin), in the cytosol [fukutin related protein (FKRP), calpain 3, myotonic dystrophy type 1 (DM1) protein kinase (DMPK) and desmin], at the sarcomere (titin) and in the nucleus [laminAC, poly(A)-binding protein nuclear 1 (PABPN1) and emerin] of striated muscle cells. Interestingly, these proteins are not always muscle specific and are often ubiquitous: for example, the nuclear membrane protein emerin involved in Emery Dreifuss muscular dystrophy, the ubiquitous PABPN1 protein in oculopharyngeal muscular dystrophy (OPMD) or the dysferlin in limb-girdle muscular dystrophy. For many of these diseases, the pathophysiological mechanisms leading from the genetic mutation to the development of the dystrophic features are still unknown. In this section, we summarize the main muscular dystrophies in children and adults: a classification based on the pattern of muscle weakness and a multiorgan implication is proposed (Table 2). Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy. DMD is an X-linked genetic disease affecting 1 in 3500 male births. DMD is caused by mutations in the dystrophin gene. Dystrophin is responsible for the maintenance of muscle fibre integrity, mediation of cytoplasmic signalling cascades and muscle functions [22–24]. Ambulation is usually lost between 10 and 12 years of age, and pulmonary insufficiency associated with cardiac involvement is the most frequent cause of death. In Becker muscular dystrophy, the allelic form of DMD, the distribution of muscle wasting and weakness is somehow similar to that in DMD, but the age of onset is around 8 years, and the course of the disease is more benign. Emery–Dreifuss muscular dystrophy (EDMD) is characterized by a triad of manifestations: i) early contractures of the Achilles tendons, elbows and posterior cervical muscles; ii) slowly progressive muscle wasting and weakness with a humeroperoneal distribution; iii) cardiomyopathy that usually presents as cardiac conduction defects, and starts by 30 years of age [25]. The X-linked form of EDMD is caused by mutations of the STA gene at Xq28, which encodes the nuclear membrane protein emerin [26]. The autosomal dominant type of this disorder is NAN 2015; 41: 270–287

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Table 2. Classification of muscular dystrophies

MD

Mode of inheritance

Age of onset

CPK

Childhood Adult

Very elevated Elevated

LGMD

X-linked X-linked or AD/AR AD/AR

Childhood Adult

Elevated

FSHD

AD

Childhood Adult

DM1

AD

OPMD

AD

Congenital Childhood Adult Late onset Adult

Normal or slightly elevated Normal or slightly elevated

DMD EDMD

Normal or slightly elevated

Weakness skeletal muscular distribution

Cardiac muscle involvement

Respiratory muscle involvement

Other systemic involvement

Lower limb-girdle Humero peronea distribution Upper and lower limb-girdle Facial and upper and lower limb-girdle

Yes Yes

Yes Possible

Brain* No

Possible

Possible

No

No

No

Retinal disease Hear

Distal or limb-girdle

Yes

Yes

Endocrine Brain Cataracts

Eyelid/pharyngeal

No

No

No

*Depending on exon type mutation. AD, autosomal dominant; AR, autosomal recessive; CPK, creatine phosphokinase.

clinically very similar but is caused by mutations of the LMNA gene at 1q21. This gene encodes lamins A and C, which make up part of the nuclear lamina [27]. Limb-girdle muscular dystrophy (LGMD) is typically an inherited disorder, with a dominant or recessive, genetic defect. LGMDs are mainly characterized by weakness of the proximal limb-girdle muscles, associated to myoglobinuria, pain, myotonia, cardiomyopathy, elevated serum creatine kinase (CK) and rippling muscles. To date, at least 20 genetically different types of LGMD have been identified, which show a great clinical and genetic heterogeneity [28]. The most common LGMD forms result from sarcolemmal adhesion complex defects, as sarcoglycans in LGMD type2 C-F, but also other sarcolemmal molecules, such as caveolin-3 in LGMD type1C and dysferlin in LGMD type 2B, or nuclear membrane, as lamin A/C in LGMD type 1B. Facioscapulohumeral muscular dystrophy (FSHD) is transmitted by an autosomal dominant inheritance associated with a contraction of the tandem 3.3-kb D4Z4 repeat unit at chromosome 4q35 [29]. Each D4Z4 repeat contains a copy of the DUX4 gene that potentially results in a toxic gain of function when expressed and appears to contribute to the pathogenesis of FSHD [30]. In FSHD, facial and shoulder girdle are the muscle groups that are mainly affected. Later, foot extensors and pelvic-girdle muscles become involved. © 2014 British Neuropathological Society

DM1, also known as Steinert’s disease, is a progressive muscle degeneration disease leading to disabling weakness and wasting with myotonia, in combination with multisystemic involvement (cataracts, cognitive impairments, cardiac and pulmonary dysfunctions). DM1 is the most common form of adult-onset neuromuscular disorder with a prevalence ranging from 2 to 14 per 100,000population worldwide. DM1 is caused by a (CTG)n microsatellite repeat expansion in the untranslated 3′ region of the DMPK gene on chromosome 19q13.3 [31]. This unstable expansion segregates as an autosomal dominant trait with incomplete penetrance and greatly variable expressivity. Four clinical forms of DM1 are recognized according to (CTG)n repeat number inversely proportional to the age of onset: congenital DM1 (>1000 CTG), childhood DM1 (21 8–17 26 8–12 18–75 18–65 6–14 None none None

− − −

2 ml divided into 26 small depots

Injection 0.5 ml each with prior electric stimulation Single injection, 1–2 ml

12 injections into an area of 10 cm2 with prior scarification

Grid of 55–60 points 1 cm apart, 0.1 ml myoblast mixture Zone of injection of 1 cm3, 25 parallel injections 5 mm grid device, 100–200 injections, 2–21 cm2 surface, in three sessions, with 2 days intervals Three parallel injections at 1 mm interdistance

5.5 ml with 55 sites around 5 tracks

80–100 sites in a grid (4 × 6 cm) spaced 5 mm apart, 2.5 cm depth 100 μl per injection, 55 sites at 5 mm intervals, 2.5 cm depth 2 or 3 injection site, 30 million cells/ml

Urethral sphincter

urethral sphincter

External anal sphincter

TA

Pharyngeal

Abductor digiti minimi

Gastrocnemius, biceps brachii, thenar eminence

12 months follow-up, safe, well-tolerated, quality of life improved 1,2,3,6and 12 months, quality of life improved in 50% of patients; 10 of 12 patients improved Follow-up for 6 months, 23.7% cured and 52.6% improvement at 6 months

Gastrocnemius was Dys+ at 18 months (PCR and IHC), very slightly the biceps brachii (PCR at 14 months). Thenar eminence was not analysed. Safety test: neither local nor systemic adverse effects were reported. Increase vascularization into 4 out of 5 treated muscles. Safe procedure, good tolerability, cell dose effect

8/9 patients Dys+ (IHC)

TA

TA

No Dys+ at 1 year follow-up but 3/8 patients showed improved strength Improved strengths (12–31%) in wrist extension at 6 months; very slight increase in Dys expression 3/4 patients Dys+ (IHC and WB) No Dys+ 1/12 patients Dys+ (IHC) 3/10 patients Dys+ (PCR) at 1 month; 1/6 at 6 months 0/3 Dys+ (IHC) at 6 months

Biceps brachii

[131]

[129]

− [130]

−

[128]

[127]

[67]

[126]

[125]

[121] [122] [123] [124]

[120]

[119]

[118]

[117]

Ref.

Myoblast Myoblast Myoblast Myoblast Myoblast Myoblast Myoblast Myoblast Myoblast Myoblast Myoblast CD133+ Myoblast Myoblast HLA-identical allogenic mesoangiblasts Myoblast Myoblast Myoblast

Cell type

7/9 patients (TA) Dys+ (IHC/WB) + 4/9 showed improved strength at 4 months 3/8 patients Dys+ (PCR) at 1 month

A A A

H H H H* H H H H H H H A A A H

Autologous/ heterologous

Extensor carpi radialis, biceps brachii Biceps brachii, TA TA Biceps brachii TA

TA, biceps brachii, and/or extensor carpi radialis longus TA

Outcomes

None None Cyclophosphamide for 6–12 months None None Cyclosporine (5 days before and 6 months after) Cyclosporine Cyclosporine for 7 days Cyclosporine 2 months before and 1 year after Tacrolimus (7 days before and maintained throughout the study) Tacrolimus (7 days before and maintained throughout the study) None None None

− − + − − + 6 patients + 6 patients + + + + − − − +

Recipient muscle

Immunosuppression regime

Immunosuppression

Mode of injection

Patients’ age

*Donor was the monozygotic twin of symptomatic carrier. A, autologous; BMD, Becker muscular dystrophy; DMD, Duchenne muscular dystrophy; FSHD, Facioscapulohumeral dystrophy; H, heterologous; IHC, immunohistochemistry; im, intramuscular; ia, intraarterial; WB, Western blot; EBD, extensor digitorum brevis; OPMD, oculopharyngeal muscular dystrophy; SCM, sterno-cleido-mastoidien; TA, tibialis anterior.

Biceps brachii

Deltoid

1993

0.5–1g

Anal incontinence Stress urinary incontinence Stress urinary incontinence

1993

−

Biceps

1992

Donor muscle

Year

1992

Muscle biopsy weight

Frudinger Sebe Blaganje

2009 2011 2013

DMD DMD DMD DMD DMD DMD DMD DMD BMD DMD DMD DMD OPMD FSHD DMD

Huard Gussoni Karpati Tremblay Tremblay Morandi Mendell Miller Neumeyer Skuk Skuk Torrente Perie

1992 1992 1993 1993 1993 1995 1995 1997 1998 2004–2006 2007 2007 2013 Ongoing Ongoing

Disease

First author

Year

Table 3. Muscle cell therapy clinical studies (cardiac muscle target is not included)

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bottlenecks have been rapidly identified in preclinical and clinical studies. The lessons we learned from over 25 years of research in this field tell us that each pathological situation has to be considered individually and that therapeutic strategies will have to be adapted to each unique situation. For example, the lack of clinical benefit of myoblast implantation in DMD patients should be compared with the clinical improvement observed in OPMD patients after implantation of the same cell type. If limited targets – such as those in OPMD – can already be treated by cell therapy, extended treatment – such as those required for other muscle dystrophies including DMD – will require further research efforts. Over the past years, many different cell types with a myogenic potential were described. A particular effort will have to be made on the research conducted to find cell types that can be systemically delivered. In addition, we should synergize the different therapeutic strategies developed in the past to make profit of all the progresses made in gene, cell or pharmacotherapy. As an example, autologous cell transplantation may require gene correction of the cells before implantation. Pharmacological treatments of the recipient muscle, to improve muscle function, may also increase the overall efficiency of gene or cell therapy strategies. A combination of all these tools will be instrumental in fighting these devastating diseases.

Acknowledgements The authors acknowledge Jean-Thomas Vilquin for fruitful discussions. This study was supported by grants from AFM (Association Française contre les Myopathies, OPMD Network Research Program 15123), MYOAGE (contract HEALTH-F2-2009-223576) from the 7th FP, the ANR Genopath-INAFIB, Fondation de l’avenir (project ET1622), INSERM, CNRS and Université Pierre et Marie Curie.

Authors contribution EN, TG, AB, VM, GBB and CT contributed equally to the writing of the manuscript and generation of the tables.

Conflicts of interest None.

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Received 1 July 2014 Accepted after revision 14 November 2014 Published online Article Accepted on 18 November 2014

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