Duchenne muscular dystrophy is the most common and severe form of progressive muscular dystrophy. Previous results showed an increased survival in double knockout mice (dko) when treated with adipose-derived CD146+ cells. In this study, we analyzed the effect of CD146+ cells compared to mesenchymal stem/stromal cells (MSCs) derived from the same human adipose sample when injected in the dko mouse model without immunosuppression. Both CD146+ cells and MSCs increased the survival of treated mice when compared to vehicle-injected mice, with a more prominent effect of CD146+ cells than MSCs. Both CD146+ cells and MSCs suppressed peripheral blood mononuclear cell proliferation, indicating immunomodulatory properties. Co-culture experiments showed that MSCs have a more inflammatory profile expression, and angiogenesis assay showed that CD146+ cells can improve blood vessel formation. CD146+ cells can extend survival of muscular dystrophy mice more efficiently than MSCs, possibly due to immunomodulatory and angiogenic properties. Further investigations focusing on exogenous CD146+ cell role in vivo will improve cell therapy understanding and effectiveness.
Get full access to this article
View all access options for this article.
References
1.
AdmyreC., AxelssonL.-G., von SteinO., and ZargariA. (2015). Immunomodulatory oligonucleotides inhibit neutrophil migration by decreasing the surface expression of interleukin-8 and leukotriene B4 receptors. Immunology, 144, 206–217.
2.
ArahataK., and EngelA.G. (1984). Monoclonal antibody analysis of mononuclear cells in myopathies. I: quantitation of subsets according to diagnosis and sites of accumulation and demonstration and counts of muscle fibers invaded by T cells. Ann Neurol, 16, 193–208.
3.
ArpanI., WillcocksR.J., ForbesS.C., FinkelR.S., LottD.J., RooneyW.D., et al. (2014). Examination of effects of corticosteroids on skeletal muscles of boys with DMD using MRI and MRS. Neurology, 83, 974–980.
4.
AssoniA., CoattiG., ValadaresM.C., BeccariM, GomesJ., PelattiM., et al. (2017). Different donors mesenchymal stromal cells secretomes reveal heterogeneous profile of relevance for therapeutic use. Stem Cells Dev, 26, 206–214.
5.
BirbrairA., ZhangT., WangZ.-M., MessiM.L., MintzA., and DelbonoO. (2013). Type-1 pericytes participate in fibrous tissue deposition in aged skeletal muscle. Am J Physiol Cell Physiol, 305, C1098–C1113.
6.
BirbrairA., ZhangT., WangZ.-M., MessiM.L., MintzA., and DelbonoO. (2014a). Pericytes: multitasking cells in the regeneration of injured, diseased, and aged skeletal muscle. Front Aging Neurosci, 6, 245.
7.
BirbrairA., ZhangT., WangZ.-M., MessiM.L., OlsonJ.D., MintzA, et al. (2014b). Type-2 pericytes participate in normal and tumoral angiogenesis. Am J Physiol Cell Physiol, 307, C25–C38.
8.
BushbyK, FinkelR., BirnkrantD.J., CaseL.E., ClemensP.R., CripeL., et al. (2010). Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol, 9, 77–93.
9.
CaplanA.I. (2017). Mesenchymal stem cells: time to change the name!. Stem Cells Transl Med, 6, 1445–1451.
10.
CaplanA.I., and SorrellJ.M. (2015). The MSC curtain that stops the immune system. Immunol Lett, 168, 136–139.
11.
ChenC.-W., OkadaM., ProtoJ.D., GaoX., SekiyaN., BeckmanS.A., et al. (2013). Human pericytes for ischemic heart repair. Stem Cells, 31, 305–316.
12.
CoattiG.C., FranginiM., ValadaresM.C., GomesJ.P., LimaN.O., CavaçanaN., et al. (2017). Pericytes extend survival of ALS SOD1 mice and induce the expression of antioxidant enzymes in the murine model and in IPSCs derived neuronal cells from an ALS patient. Stem Cell Rev, 13, 686–698.
13.
CorselliM., ChenC.-W., CrisanM., LazzariL., and PéaultB. (2010). Perivascular ancestors of adult multipotent stem cells. Arterioscler Thromb Vasc Biol, 30, 1104–1109.
14.
CorselliM., ChinC.J, ParekhC., SahaghianA., WangW., GeS., et al. (2013). Perivascular support of human hematopoietic stem/progenitor cells. Blood, 121, 2891–2901.
15.
CrisanM., YapS., CasteillaL., ChenC.-W., CorselliM., ParkT.S, et al. (2008). A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell, 3, 301–313.
16.
DaviesK.E., and GroundsM.D. (2006). Treating muscular dystrophy with stem cells?. Cell, 127, 1304–1306.
17.
DellavalleA., SampaolesiM., TonlorenziR., TagliaficoE., SacchettiB., PeraniL., et al. (2007). Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells. Nat Cell Biol, 9, 255–267.
18.
EmeryA. (2002a). The muscular dystrophies. Lancet, 359, 687–695.
19.
EmeryA. (2002b). Muscular dystrophy into the new millennium. Neuromuscul Disord, 12, 343–349.
20.
JoblingA.I., and AugusteynR.C. (2002). What causes steroid cataracts?. A review of steroid-induced posterior subcapsular cataracts. Clin Exp Optom, 85, 61–75.
21.
KyurkchievD., BochevI., Ivanova-TodorovaE., MourdjevaM., OreshkovaT., BelemezovaK., et al. (2014). Secretion of immunoregulatory cytokines by mesenchymal stem cells. World J Stem Cells, 6, 552–570.
22.
LavasaniM., RobinsonA.R., LuA., SongM., FeduskaJ.M., AhaniB., et al. (2012). Muscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model. Nat Commun, 3, 608.
23.
LimaB.L., SantosE.J.C., FernandesG.R., MerkelC., MelloM.R.B., GomesJ.P.A., SoukoyanM., KerkisA., MassironiS.M.G., VisintinJ.A., and PereiraL.V. (2010). A new mouse model for marfan syndrome presents phenotypic variability associated with the genetic background and overall levels of Fbn1 expression. Plos One, 5, e14136.
24.
Meirelles, Lda.S., FontesA.M., CovasD.T., and CaplanA.I. (2009). Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev, 20, 419–427.
25.
MurrayI.R., WestC.C., HardyW.R., JamesA.W., ParkT.S., NguyenA., et al. (2014). Natural history of mesenchymal stem cells, from vessel walls to culture vessels. Cell Mol Life Sci, 71, 1353–1374.
26.
RodriguezA.-M., PisaniD., DechesneC.A., Turc-CarelC., KurzenneJ.-Y., WdziekonskiB., et al. (2005). Transplantation of a multipotent cell population from human adipose tissue induces dystrophin expression in the immunocompetent Mdx mouse. J Exp Med, 201, 1397–1405.
27.
RougerK., LarcherT., DubreilL., DeschampsJ.-Y., Le GuinerC., JouvionG., et al. (2011). Systemic delivery of allogenic muscle stem cells induces long-term muscle repair and clinical efficacy in Duchenne muscular dystrophy dogs. Am J Pathol, 179, 2501–2518.
28.
SeccoM., BuenoC., VieiraN.M., AlmeidaC., PelattiM., ZucconiE., et al. (2013). Systemic delivery of human mesenchymal stromal cells combined with IGF-1 enhances muscle functional recovery in LAMA2 dy/2j dystrophic mice. Stem Cell Rev, 9, 93–109.
29.
SerraF., QuartaM., CanatoM., TonioloL., De ArcangelisV., TrottaA., et al. (2012). Inflammation in muscular dystrophy and the beneficial effects of non-steroidal anti-inflammatory drugs. Muscle Nerve, 46, 773–784.
30.
SpencerM.J., and TidballJ.G. (2001). Do immune cells promote the pathology of dystrophin-deficient myopathies?. Neuromuscul Disord, 11, 556–564.
31.
TammaR., AnneseT., CapogrossoR.F., CozzoliA., BenagianoV., SblendorioV., et al. (2013). Effects of prednisolone on the dystrophin-associated proteins in the blood-brain barrier and skeletal muscle of dystrophic Mdx mice. Lab Invest, 93, 592–610.
32.
ValadaresM.C., GomesJ.P., CastelloG., et al. (2014). Human adipose tissue derived pericytes increase life span in Utrn (tm1Ked) Dmd (Mdx)/J mice. Stem Cell Rev, 10, 830–840.
33.
VieiraN.M., BrandaliseV., ZucconiE., JazedjeT., SeccoM., NunesV.A., et al. (2008a). Human multipotent adipose-derived stem cells restore dystrophin expression of Duchenne skeletal-muscle cells in vitro. Biol Cell, 100, 231–241.
34.
VieiraN.M., BuenoC.R., BrandaliseV., MoraesL.V., ZucconiE., SeccoM., et al. (2008b). SJL dystrophic mice express a significant amount of human muscle proteins following systemic delivery of human adipose-derived stromal cells without immunosuppression. Stem Cells, 26, 2391–2398.
35.
VieiraN.M., ValadaresM., ZucconiE., SeccoM., BuenoC.R., BrandaliseV., et al. (2012). Human adipose-derived mesenchymal stromal cells injected systemically into GRMD dogs without immunosuppression are able to reach the host muscle and express human dystrophin. Cell Transplant, 21, 1407–1417.
36.
VieiraN.M., ZucconiE., BuenoC.R., SeccoM., SuzukiM.F., BartoliniP., et al. (2010). Human multipotent mesenchymal stromal cells from distinct sources show different in vivo potential to differentiate into muscle cells when injected in dystrophic mice. Stem Cell Rev, 6, 560–566.
37.
WatermanR.S., TomchuckS.L., HenkleS.L., and BetancourtA.M. (2010). A New mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an immunosuppressive MSC2 phenotype. PloS One, 5, e10088.
38.
ZhangY., ZhuY., LiY., CaoJ., ZhangH., ChenM., et al. (2015). Long-term engraftment of myogenic progenitors from adipose-derived stem cells and muscle regeneration in dystrophic mice. Hum Mol Genet, 24, 6029–6040.
39.
ZimmerlinL., DonnenbergV.S., RubinJ.P., and DonnenbergA.D. (2013). Mesenchymal markers on human adipose stem/progenitor cells. Cytometry A, 83A, 134–140.
40.
ZucconiE., VieiraN.M, BuenoC.R., SeccoM., JazedjeT., ValadaresM.C., et al. (2011). Preclinical studies with umbilical cord mesenchymal stromal cells in different animal models for muscular dystrophy. J Biomed Biotechnol, 2011, 715251.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
