Abstracts
Mesenchymal stem cells (MSCs) are multipotent progenitor cells that have the capacity to differentiate into all lineages of mesodermal origin, e.g., cartilage, bone, and adipocytes. MSCs have been identified at different stages of development, including adulthood, and in different tissues, such as bone marrow, adipose tissue and umbilical cord. Recent studies have shown that MSCs have the ability to migrate to injured sites. In this regard, an important characteristic of MSCs is their immunomodulatory and anti-inflammatory effects. For instance, there is evidence that MSCs can regulate the immune system by inhibiting proliferation of T and B cells. Clinical interest in the use of MSCs has increased considerably over the past few years, especially because of the ideal characteristics of these cells for regenerative medicine. Therapies with MSCs have shown promising results neurodegenerative diseases, in addition to regulating inflammation, they can promote other beneficial effects, such as neuronal growth, decrease free radicals, and reduce apoptosis. Notwithstanding, despite the vast amount of research into MSCs in neurodegenerative diseases, the mechanism of action of MSCs are still not completely clarified, hindering the development of effective treatments. Conversely, studies in models of psychiatric disorders are scarce, despite the promising results of MSCs therapies in this field as well.
Mesenchymal stem cells; treatment; neurodegenerative disease; psychiatric disorders
Células tronco mesenquimais (CTMs) são células progenitoras multipotentes que têm a capacidade de se diferenciar em todas as linhagens de origem mesodérmica, como, cartilagem, ossos, e adipócitos. CTMs têm sido identificadas em diferentes fases do desenvolvimento, incluindo a idade adulta e em diferentes tecidos, tais como medula óssea, tecido adipose e cordão umbilical. Estudos recentes têm mostrado que as CTMs possuem a capacidade de migrar para locais de lesões. Nesse sentido, uma característica importante das CTMs são os seus efeitos imunomodulatórios e anti-inflamatórios. Por exemplo, há evidências que as CTMs podem regular o sistema imune por inibição da proliferação de células T e B. O interesse clínico no uso das CTMs tem aumentado consideravelmente nos últimos anos, especialmente devido às características ideais destas células para a medicina regenerativa. Terapias com CTMs têm mostrado resultados promissores em doenças neurodegenerativas, além de regular a inflamação, elas podem promover outros efeitos benéficos, tais como, crescimento neuronal, diminuição de radicais livres e reduzir a apoptose. No entanto, apesar de muitas pesquisas das CTMs em doenças neurodegenerativas, o mecanismo de ação das CTMs ainda não estão completamente esclarecidos, o que dificulta o desenvolvimento de tratamentos eficazes. Por outro lado, estudos em modelos de doenças psiquiátricas são escassos, apesar dos resultados promissores utilizando terapias com CTMs nesta área.
Células-tronco mesenquimais; tratamento; doença neurodegenerativa; transtornos psiquiátricos
INTRODUCTION
Mesenchymal stem cells were first described by Friedenstein as "colony forming units-fibroblastic" due to their ability to generate single cell-derived colonies (Friedenstein et al. 1976FRIEDENSTEIN AJ, GORSKAJA JF AND KULAGINA NN. 1976. Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp Hematol 4: 267-274.). Subsequently, authors have used different names to refer to these structures, and only in the 2000s did the committee of the International Society of Cytotherapy propose the name "multipotent mesenchymal stromal cells". Since then, authors have simply referred to them as mesenchymal stem cells (MSCs) (Dominici et al. 2006DOMINICI M, LE BLANC K, MUELLER I, SLAPER-CORTENBACH I, MARINI F, KRAUSE D, DEANS R, KEATING A, PROCKOP D AND HORWITZ E. 2006. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8: 315-317.).
MSCs are multipotent progenitor cells that have the capacity to differentiating into all lineages of mesodermal origin, e.g., cartilage, bone, and adipocytes (Pittenger et al. 1999PITTENGER MF, MACKAY AM, BECK SC, JAISWAL RK, DOUGLAS R, MOSCA JD, MOORMAN MA, SIMONETTI DW, CRAIG S AND MARSHAK DR. 1999. Multilineage potential of adult human mesenchymal stem cells. Science 284: 143-147.). Recent studies have shown that MSCs are also able to differentiate into cells from sources other than mesodermal, such as neurons and hepatocytes (Dezawa et al. 2004DEZAWA M ET AL. 2004. Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation. J Clin Invest 113:12 1701-1710., Hermann et al. 2004HERMANN A ET AL. 2004. Efficient generation of neural stem cell-like cells from adult human bone marrow stromal cells. J Cell Sci 117: 4411-4422., Perrier et al. 2004PERRIER AL, TABAR V, BARBERI T, RUBIO ME, BRUSES J, TOPF N, HARRISON NL AND STUDER L. 2004. Derivation of midbrain dopamine neurons from human embryonic stem cells. Proc Natl Acad Sci USA 101: 12543-12548., Sato et al. 2005SATO Y ET AL. 2005. Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion. Blood 106: 756-763.). MSCs have been identified at different stages of development, including adulthood, and in different tissues, such as bone marrow, adipose tissue, bone, lung, liver, teeth, skeletal muscle, amniotic fluid, umbilical cord, and cord blood (Campagnoli et al. 2001CAMPAGNOLI C, ROBERTS IA, KUMAR S, BENNETT PR, BELLANTUONO I AND FISK NM. 2001. Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood 98: 2396-2402., da Silva Meirelles et al. 2006DA SILVA MEIRELLES L, CHAGASTELLES PC AND NARDI NB. 2006. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci 119: 2204-2213., Erices et al. 2000ERICES A, CONGET P AND MINGUELL JJ. 2000. Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol 109: 235-242., Lee et al. 2004LEE OK, KUO TK, CHEN WM, LEE KD, HSIEH SL AND CHEN TH. 2004. Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood 103: 1669-1675.).
Three basic criteria have been established by the International Society of Cellular Therapy to determine whether ex vivo expanded cells could be considered MSCs; namely: 1) ability to adhere to plastic in cell culture; 2) capacity to differentiate into osteoblasts, adipocytes, and chondrocytes in vitro; and 3) expression of specific surface membrane molecules (CD73, CD90, CD105), simultaneous lack of expression of hematopoietic markers (CD14, CD34, CD45) and human leukocyte antigen DR (HLA-DR) (Dominici et al. 2006DOMINICI M, LE BLANC K, MUELLER I, SLAPER-CORTENBACH I, MARINI F, KRAUSE D, DEANS R, KEATING A, PROCKOP D AND HORWITZ E. 2006. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8: 315-317.).
Due to their differentiation, self-renewal, and immune-suppressive abilities, MSCs have received increasing attention from investigators with regard to their potential use as cell therapy in different conditions, including ischemia, diabetes, and even neurological diseases (Drela et al. 2013DRELA K, SIEDLECKA P, SARNOWSKA A AND DOMANSKA-JANIK K. 2013. Human mesenchymal stem cells in the treatment of neurological diseases. Acta Neurobiol Exp (Wars) 73: 38-56., Ezquer et al. 2008EZQUER FE, EZQUER ME, PARRAU DB, CARPIO D, YANEZ AJ AND CONGET PA. 2008. Systemic administration of multipotent mesenchymal stromal cells reverts hyperglycemia and prevents nephropathy in type 1 diabetic mice. Biol Blood Marrow Transplant 14: 631-640., Honma et al. 2006HONMA T, HONMOU O, IIHOSHI S, HARADA K, HOUKIN K, HAMADA H AND KOCSIS JD. 2006. Intravenous infusion of immortalized human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat. Exp Neurol 199: 56-66., Horwitz et al. 1999HORWITZ EM ET AL. 1999. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 5: 309-313., Phinney Prockop 2007PHINNEY DG AND PROCKOP DJ. 2007. Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair current views. Stem Cells 25: 2896-2902.). Therapies can consist of the implantation of exogenous cells to the injured site, or the release of trophic factors that will assist in the endogenous regeneration of the injured region (Sohni and Verfaillie 2013SOHNI A AND VERFAILLIE CM. 2013. Mesenchymal Stem Cells Migration Homing and Tracking. Stem Cells Int 2013: 130763.).
MIGRATION OF MSCs
Recent studies have shown that MSCs have the ability to migrate to injured sites (Chapel et al. 2003CHAPEL A ET AL. 2003. Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radiation-induced multi-organ failure syndrome. J Gene Med 5: 1028-1038., Wang et al. 2002WANG L, LI Y, CHEN X, CHEN J, GAUTAM SC, XU Y AND CHOPP M. 2002. MCP-1, MIP-1, IL-8 and ischemic cerebral tissue enhance human bone marrow stromal cell migration in interface culture. Hematology 7: 113-117.). MSCs migration mechanisms involve the expression of specific receptors to facilitate reaching the target site, adhering to and infiltrating the damaged organ or tissue. In this line, an important issue in MSCs therapy is the way that cells will reach the site of damage, a process denominated "homing." Therapy effectiveness depend directly on the cells' ability to produce trophic factors, such as growth factors and cytokines that will assist in the regeneration of endogenous cells. For this to occur, correct migration of cells to the injured tissue is of utmost importance. Important factors such as age, number of cell passages, number of cells, and the protocols used for cell delivery are crucial for the migration and homing processes to be successful (Ries et al. 2007RIES C, EGEA V, KAROW M, KOLB H, JOCHUM M AND NETH P. 2007. MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells: differential regulation by inflammatory cytokines. Blood 109: 4055-4063., Rombouts and Ploemacher 2003ROMBOUTS WJ AND PLOEMACHER RE. 2003. Primary murine MSC show highly efficient homing to the bone marrow but lose homing ability following culture. Leukemia 17: 160-170.).
So far, the gold standard delivery method in the administration of MSCs is intravenous infusion (Akiyama et al. 2002AKIYAMA Y, RADTKE C AND KOCSIS JD. 2002. Remyelination of the rat spinal cord by transplantation of identified bone marrow stromal cells. J Neurosci 22: 6623-6630., Nomura et al. 2005NOMURA T, HONMOU O, HARADA K, HOUKIN K, HAMADA H AND KOCSIS JD. 2005. I.V. infusion of brain-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat. Neuroscience 136: 161-169.). Notwithstanding, research continues to try to improve homing and migration, with the goal of increasing the number of MSCs capable of reaching the target site and consequently improving MSCs transplantation protocols for specific clinical applications (Cheng et al. 2008CHENG Z ET AL. 2008. Targeted migration of mesenchymal stem cells modified with CXCR4 gene to infarcted myocardium improves cardiac performance. Mol Ther 16: 571-579., Choi et al. 2010CHOI YJ, LI WY, MOON GJ, LEE PH, AHN YH, LEE G AND BANG OY. 2010. Enhancing trophic support of mesenchymal stem cells by ex vivo treatment with trophic factors. J Neurol Sci 298: 28-34., Gerrits et al. 2010GERRITS A, DYKSTRA B, KALMYKOWA OJ, KLAUKE K, VEROVSKAYA E, BROEKHUIS MJ, DE HAAN G AND BYSTRYKH LV. 2010. Cellular barcoding tool for clonal analysis in the hematopoietic system. Blood 115: 2610-2618., Grayson et al. 2007GRAYSON WL, ZHAO F, BUNNELL B AND MA T. 2007. Hypoxia enhances proliferation and tissue formation of human mesenchymal stem cells. Biochem Biophys Res Commun 358: 948-953., Maijenburg et al. 2011MAIJENBURG MW ET AL. 2011. Nuclear receptors Nur77 and Nurr1 modulate mesenchymal stromal cell migration. Stem Cells Dev 21: 228-238.).
MSCs SECRETOME AND PARACRINE ACTIVITY
In addition to their differentiation potential and the migratory properties that enable tissue replacement (Mafi et al. 2011MAFI R, HINDOCHA S, MAFI P, GRIFFIN M AND KHAN WS. 2011. Sources of adult mesenchymal stem cells applicable for musculoskeletal applications - a systematic review of the literature. Open Orthop J 5: 242-248., Quevedo et al. 2009QUEVEDO HC ET AL. 2009. Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity. Proc Natl Acad Sci USA 106: 14022-14027.), MSCs have broad immunomodulatory properties (Aggarwal and Pittenger 2005AGGARWAL S AND PITTENGER MF. 2005. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105: 1815-1822., Menard and Tarte 2013MENARD C AND TARTE K. 2013. Immunoregulatory properties of clinical grade mesenchymal stromal cells: evidence, uncertainties, and clinical application. Stem Cell Res Ther 4: 64.) and paracrine activities (Mureli et al. 2013MURELI S, GANS CP, BARE DJ, GEENEN DL, KUMAR NM AND BANACH K. 2013. Mesenchymal stem cells improve cardiac conduction by upregulation of connexin 43 through paracrine signaling. Am J Physiol Heart Circ Physiol 304: H600-609., Waszak et al. 2012WASZAK P, ALPHONSE R, VADIVEL A, IONESCU L, EATON F AND THEBAUD B. 2012. Preconditioning enhances the paracrine effect of mesenchymal stem cells in preventing oxygen-induced neonatal lung injury in rats. Stem Cells Dev 21: 2789-2797.). These characteristics have been associated with the therapeutic effects of MSCs and have been investigated with a focus on potential clinical applications.
The MSCs secretome includes the molecules released by MSCs in response to injury that directly or indirectly promote repair, e.g., growth factors, cytokines, antioxidants, and extracellular matrix proteins (Chan and Lam 2013CHAN JK AND LAM PY. 2013. Human mesenchymal stem cells and their paracrine factors for the treatment of brain tumors. Cancer Gene Ther 20: 539-543., Chen et al. 2008CHEN L, TREDGET EE, WU PY AND WU Y. 2008. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One 3: e1886.). Some conditions that lead to tissue damage, such as pro-inflammatory or hypoxic stimuli and exposure to apoptotic factors, increase the secretion of specific factors by MSCs, which act on angiogenesis, neurogenesis and regulate neural niche environment, mediating protection and repair processes (Chen et al. 2003CHEN J, ZHANG ZG, LI Y, WANG L, XU YX, GAUTAM SC, LU M, ZHU Z AND CHOPP M. 2003. Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. Circ Res 92: 692-699., 2002CHEN X, LI Y, WANG L, KATAKOWSKI M, ZHANG L, CHEN J, XU Y, GAUTAM SC AND CHOPP M. 2002. Ischemic rat brain extracts induce human marrow stromal cell growth factor production. Neuropathology 22: 275-279., Rosova et al. 2008ROSOVA I, DAO M, CAPOCCIA B, LINK D AND NOLTA JA. 2008. Hypoxic preconditioning results in increased motility and improved therapeutic potential of human mesenchymal stem cells. Stem Cells 26: 2173-2182.).
Evidence has suggested that MSCs have the potential to show paracrine activity even without direct cell contact. For instance, studies have demonstrated that MSCs conditioned medium was able to protect neurons from inflammation in the absence of engraftment, suggesting a neuroprotective effect through secretion of neurotrophic factors even at a distance from the damaged organ (Bai et al. 2012BAI L, LENNON DP, CAPLAN AI, DECHANT A, HECKER J, KRANSO J, ZAREMBA A AND MILLER RH. 2012. Hepatocyte growth factor mediates mesenchymal stem cell-induced recovery in multiple sclerosis models. Nat Neurosci 15: 862-870., Uccelli and Prockop 2010UCCELLI A AND PROCKOP DJ. 2010. Why should mesenchymal stem cells (MSCs) cure autoimmune diseases? Curr Opin Immunol 22:768-774.). Some of these factors with protective effects have been identified, namely: stem cell-secreted hepatocyte growth factor (HGF), fibroblast growth factor (FGF)-II, brain-derived neurotrophic factor (BDNF), and platelet-derived growth factor (PDGF)-AB (Bai et al. 2012, Constantin et al. 2009CONSTANTIN G ET AL. 2009. Adipose-derived mesenchymal stem cells ameliorate chronic experimental autoimmune encephalomyelitis. Stem Cells 27: 2624-2635., Voulgari-Kokota et al. 2012VOULGARI-KOKOTA A, FAIRLESS R, KARAMITA M, KYRARGYRI V, TSEVELEKI V, EVANGELIDOU M, DELORME B, CHARBORD P, DIEM R AND PROBERT L. 2012. Mesenchymal stem cells protect CNS neurons against glutamate excitotoxicity by inhibiting glutamate receptor expression and function. Exp Neurol 236: 161-170.). MSCs-secreted BDNF and nerve growth factor beta (β-NGF), for instance, have promoted cell resilience and neuritogenesis in co-culture experiments (Crigler et al. 2006CRIGLER L, ROBEY RC, ASAWACHAICHARN A, GAUPP D AND PHINNEY DG. 2006. Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis. Exp Neurol 198: 54-64.). The characterization of MSCs conditioned media has pointed to insulin-like growth factor 1 (IGF-1), HGF, vascular endothelial growth factor (VEGF), and transforming growth factor beta (TGF-β) (Nakano et al. 2010NAKANO N ET AL. 2010. Characterization of conditioned medium of cultured bone marrow stromal cells. Neurosci Lett 483: 57-61.), but other factors involved in the MSCs secretome remain to be identified.
MSCs can also secrete vesicles containing important molecules such as cytokines, in addition to isolated paracrine soluble factors. These vesicles act via paracrine or endocrine signaling, however, their composition and role remain to be established (Biancone et al. 2012BIANCONE L, BRUNO S, DEREGIBUS MC, TETTA C AND CAMUSSI G. 2012. Therapeutic potential of mesenchymal stem cell-derived microvesicles. Nephrol Dial Transplant 27: 3037-3042., Camussi et al. 2013CAMUSSI G, DEREGIBUS MC AND CANTALUPPI V. 2013. Role of stem-cell-derived microvesicles in the paracrine action of stem cells. Biochem Soc Trans 41: 283-287.). Both the soluble factors and these vesicles seem to be essential to the paracrine activity associated with MSCs.
The paracrine effects of MSCs have been studied in different animal models of neurological disorders, e.g., stroke, Parkinson's, Alzheimer's, and Huntington's diseases, and amyotrophic lateral sclerosis, as will be discussed below. The paracrine activity of MSCs could also be related to the immunomodulatory properties of these cells - two functions acting together for brain protection and regeneration (Fig. 1).
- Schematic figure to show the mechanism of action of MSCs in the CNS. The MSCs has been described to release neurotrophic factors and anti-inflammatories cytokines (BDNF, GDNF, VEGF, TGF-β1, IL-10, IL-6). These molecules act as an assistant in the nervous tissue regeneration through the activation of neurogenesis, neuroprotection, immunomodulation in astrocyte, oligodendrocyte and neuron. Furthermore can inactivating cell death through apoptosis.
MSCs SECRETOME AND IMMUNOMODULATION
An important characteristic of MSCs is their significant immunomodulatory and anti-inflammatory effects. For instance, evidence has shown that MSCs can regulate the immune system by inhibiting the proliferation of T and B cells (Duffy et al. 2011DUFFY MM, RITTER T, CEREDIG R AND GRIFFIN MD. 2011. Mesenchymal stem cell effects on T-cell effector pathways. Stem Cell Res Ther 2: 34., Franquesa et al. 2012FRANQUESA M, HOOGDUIJN MJ, BESTARD O AND GRINYO JM. 2012. Immunomodulatory effect of mesenchymal stem cells on B cells. Front Immunol 3: 212.), natural killer (NK) cells (Di Nicola et al. 2002DI NICOLA M, CARLO-STELLA C, MAGNI M, MILANESI M, LONGONI PD, MATTEUCCI P, GRISANTI S AND GIANNI AM. 2002. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99: 3838-3843., Spaggiari et al. 2008SPAGGIARI GM, CAPOBIANCO A, ABDELRAZIK H, BECCHETTI F, MINGARI MC AND MORETTA L. 2008. Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 111: 1327-1333.) and neutrophil apoptosis (Raffaghello et al. 2008RAFFAGHELLO L, BIANCH G, BERTOLOTTO M, MONTECUCCO F, BUSCA A, DALLEGRI F, OTTONELLO L AND PISTOIA V. 2008. Human mesenchymal stem cells inhibit neutrophil apoptosis: a model for neutrophil preservation in the bone marrow niche. Stem Cells 26: 151-162.). Via this mechanism, MSCs influence the production and secretion of antibodies by B cells, cytokine secretion, and NK cytotoxicity (Aggarwal and Pittenger 2005AGGARWAL S AND PITTENGER MF. 2005. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105: 1815-1822., Spaggiari et al. 2008SPAGGIARI GM, CAPOBIANCO A, ABDELRAZIK H, BECCHETTI F, MINGARI MC AND MORETTA L. 2008. Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 111: 1327-1333.). MSCs have also been suggested to inhibit the differentiation of monocytes into dendritic cells and in addition to influencing the roles of these cells (Aggarwal and Pittenger 2005AGGARWAL S AND PITTENGER MF. 2005. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105: 1815-1822., Ivanova-Todorova et al. 2009IVANOVA-TODOROVA E, BOCHEV I, MOURDJEVA M, DIMITROV R, BUKAREV D, KYURKCHIEV S, TIVCHEV P, ALTUNKOVA I AND KYURKCHIEV DS. 2009. Adipose tissue-derived mesenchymal stem cells are more potent suppressors of dendritic cells differentiation compared to bone marrow-derived mesenchymal stem cells. Immunol Lett 126: 37-42.).
The mechanisms responsible for the immunosuppressive effects of MSCs have been the focus of several studies, and cell-to-cell contact and soluble factors have been indicated as key elements in this area. Among soluble factors, the following have been highlighted: nitric oxide (Sato et al. 2007SATO K, OZAKI K, OH I, MEGURO A, HATANAKA K, NAGAI T, MUROI K AND OZAWA K. 2007. Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood 109: 228-234.), indoleamine 2,3-dioxygenase (Meisel et al. 2004MEISEL R, ZIBERT A, LARYEA M, GOBEL U, DAUBENER W AND DILLOO D. 2004. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 103: 4619-4621.), TGF-β1, HGF (Di Nicola et al. 2002), interleukin-10 (IL-10), prostaglandin E2 (pGe2) (Aggarwal and Pittenger 2005AGGARWAL S AND PITTENGER MF. 2005. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105: 1815-1822.), heme oxygenase-1 (HO1), IL-6 (Kogler et al. 2005KOGLER G, RADKE TF, LEFORT A, SENSKEN S, FISCHER J, SORG RV AND WERNET P. 2005. Cytokine production and hematopoiesis supporting activity of cord blood-derived unrestricted somatic stem cells. Exp Hematol 33: 573-583.) and soluble HLA-G5 (Selmani et al. 2008SELMANI Z ET AL. 2008. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells. Stem Cells 26: 212-222.). Several studies have suggested that MSCs inhibit inflammatory processes in different disease states (Lee et al. 2009aLEE RH, PULIN AA, SEO MJ, KOTA DJ, YLOSTALO J, LARSON BL, SEMPRUN-PRIETO L, DELAFONTAINE P AND PROCKOP DJ. 2009a. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell 5: 54-63., Sanchez et al. 2011SANCHEZ L ET AL. 2011. Enrichment of human ESC-derived multipotent mesenchymal stem cells with immunosuppressive and anti-inflammatory properties capable to protect against experimental inflammatory bowel disease. Stem Cells 29: 251-262., van Koppen et al. 2012VAN KOPPEN A, JOLES JA, VAN BALKOM BW, LIM SK, DE KLEIJN D, GILES RH AND VERHAAR MC. 2012. Human embryonic mesenchymal stem cell-derived conditioned medium rescues kidney function in rats with established chronic kidney disease. PLoS One 7: e38746.), contributing to the regeneration of damaged tissues, probably by modulating the immune response.
In summary, the paracrine and immunomodulatory factors present in the MSCs secretome seem to play important roles in establishing an appropriate tissue microenvironment to promote repair in damaged situations justifying research into the therapeutic potential of these cells.
MSCs SECRETOME: CLINICAL APPLICATION
Clinical interest in the use of MSCs has increased significantly over the past few years, especially because of the ideal characteristics of these cells for regenerative medicine. Specifically, MSCs can be obtained from tissues commonly present in clinical situations (e.g., bone marrow, adipose tissue, and umbilical cord blood), they can be expanded in culture for testing purposes and for clinical use, and have low immunogenicity, which is very useful for potential clinical applications (Le Blanc et al. 2003LE BLANC K, TAMMIK C, ROSENDAHL K, ZETTERBERG E AND RINGDEN O. 2003. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 31: 890-896.).
However, before MSCs can be used in regenerative medicine, it is essential to understand the biology of these cells and investigate the most appropriate ways to culture and handle them. In addition, it is important to know in detail the properties of the molecules secreted by MSCs, through the characterization of their secretome. In this sense, gene expression, proteomics, and metabolomics have been applied to investigate the potential therapeutic action of new and already known soluble factors secreted by MSCs.
MSCs APPLICATION IN NEURODEGENERATIVE DISEASES
Despite the vast amount of research into neurodegenerative diseases over the past few years, their etiology and pathophysiology are still not completely understood. Moreover, the complexity of these conditions pose difficulties to the development of effective treatments. Inflammation has been identified as a key factor in the pathophysiology of degenerative diseases affecting the central nervous system (CNS). In these pathologies, the primary insult evokes a local inflammation, with reactive astrogliosis, macrophage influx, and cell death generating tissue damage and glial scar formation (Drela et al. 2013DRELA K, SIEDLECKA P, SARNOWSKA A AND DOMANSKA-JANIK K. 2013. Human mesenchymal stem cells in the treatment of neurological diseases. Acta Neurobiol Exp (Wars) 73: 38-56.). Therefore, immunomodulatory therapies may become a good therapeutic strategy in these cases.
MSCs therapies have shown promising results in neurodegenerative diseases. In addition to regulating inflammation, they can also promote other beneficial effects, such as neuronal growth, a decrease in free radical levels, and reduce apoptosis (Dharmasaroja 2009DHARMASAROJA P. 2009. Bone marrow-derived mesenchymal stem cells for the treatment of ischemic stroke. J Clin Neurosci 16: 12-20.). Once again, application of MSCs therapies in these scenarios may help reduce all the adverse pathological events caused by neurodegenerative diseases (Table I).
Summary of the main results using MSCs application in neurodegenerative and psychiatric diseases.
ALZHEIMER'S DISEASE
Alzheimer's disease (AD) is a devastating and the most common form of dementia, characterized by extracellular amyloid plaques, neurofibrillary tangles, and a progressive loss of neurons and synapses in different brain regions. Patients with AD present memory deficits and cognitive impairment (Ballard et al. 2011BALLARD C, GAUTHIER S, CORBETT A, BRAYNE C, AARSLAND D AND JONES E. 2011. Alzheimer's disease. Lancet 377: 1019-1031.). To date, the treatment of AD is only palliative, and involves mainly drugs to increase cerebral acetylcholine levels. MSCs therapy seems to be a very attractive option in this condition (Drela et al. 2013).
Several studies have shown promising results with the use of MSCs in animal models of AD. One study in particular showed that bone marrow-derived MSCs injected intracerebral were effective in reducing accumulation of amyloid-β (Aβ) in the brain of an animal model of AD prepared via direct Aβ injection in the hippocampal dentate gyrus (Lee et al. 2010bLEE JK, JIN HK, ENDO S, SCHUCHMAN EH, CARTER JE AND BAE JS. 2010b. Intracerebral transplantation of bone marrow-derived mesenchymal stem cells reduces amyloid-beta deposition and rescues memory deficits in Alzheimer's disease mice by modulation of immune responses. Stem Cells 28: 329-343.). The same group showed that intracerebral transplantation of bone marrow-derived MSCs to amyloid precursor protein and presenilin in double transgenic mice ameliorated cognitive function. Furthermore, mice treated with MSCs showed a decrease in hyperphosphorylated tau protein levels (Lee et al. 2010bLEE JK, JIN HK, ENDO S, SCHUCHMAN EH, CARTER JE AND BAE JS. 2010b. Intracerebral transplantation of bone marrow-derived mesenchymal stem cells reduces amyloid-beta deposition and rescues memory deficits in Alzheimer's disease mice by modulation of immune responses. Stem Cells 28: 329-343.). In another study, Lee et al. (2010a)LEE HJ, LEE JK, LEE H, SHIN JW, CARTER JE, SAKAMOTO T, JIN HK AND BAE JS. 2010a. The therapeutic potential of human umbilical cord blood-derived mesenchymal stem cells in Alzheimer's disease. Neurosci Lett 481: 30-35. reported that intracerebral injection of human umbilical cord blood-derived MSCs in an acute model of AD, improved cognitive function, reduced levels of neuronal apoptosis, and decreased activation of astrocytes and microglia (Lee et al. 2010aLEE HJ, LEE JK, LEE H, SHIN JW, CARTER JE, SAKAMOTO T, JIN HK AND BAE JS. 2010a. The therapeutic potential of human umbilical cord blood-derived mesenchymal stem cells in Alzheimer's disease. Neurosci Lett 481: 30-35.). Injection intracerebral of bone marrow-derived MSCs has also been shown to improve learning and memory in a chemically and age-induced rat model of AD (Babaei et al. 2012BABAEI P, SOLTANI TEHRANI B AND ALIZADEH A. 2012. Transplanted bone marrow mesenchymal stem cells improve memory in rat models of Alzheimer's disease. Stem Cells Int, p.369-417.). Kim et al. (2012)KIM JY ET AL. 2012. Soluble intracellular adhesion molecule-1 secreted by human umbilical cord blood-derived mesenchymal stem cell reduces amyloid-beta plaques. Cell Death Differ 19: 680-691. in turn, evaluated the mechanisms involved in Aβ degradation induced by MSCs. According to that author, soluble intracellular adhesion molecule-1 (sICAM-1) is released by human umbilical cord blood-derived MSCs and acts on microglial cells, inducing the expression of the Aβ-degrading enzyme (Kim et al. 2012KIM JY ET AL. 2012. Soluble intracellular adhesion molecule-1 secreted by human umbilical cord blood-derived mesenchymal stem cell reduces amyloid-beta plaques. Cell Death Differ 19: 680-691.).
Recently, one study showed that a single intracerebral injection of MSCs, decreased cerebral Aβ deposition compared with animals treated with phosphate buffered saline (PBS). The expression of dynamin 1 and synapsin 1, two proteins typically decreased in the brains of AD patients, were increased in the brains of AD animals treated with MSCs (Bae et al. 2013BAE JS, JIN HK, LEE JK, RICHARDSON JC AND CARTER JE. 2013. Bone marrow-derived mesenchymal stem cells contribute to the reduction of amyloid-beta deposits and the improvement of synaptic transmission in a mouse model of pre-dementia Alzheimer's disease. Curr Alzheimer Res 10: 524-531.).
Even though the results obtained with animal models have been encouraging, findings from clinical studies are not yet available.
PARKINSON'S DISEASE
Parkinson's disease (PD) is an extremely common neurodegenerative illness. This condition is characterized by the progressive loss of dopaminergic neurons in the substantia nigra and a severe decrease in striatal dopamine contents (Jenner 2008JENNER P. 2008. Functional models of Parkinson's disease: a valuable tool in the development of novel therapies. Ann Neurol 64: S16-29.). The clinical symptoms of PD include tremor, muscle rigidity, bradykinesia, and postural instability. Existing pharmacological therapies and surgeries can improve clinical symptoms at early stages, but become less effective as the disease progresses (Glavaski-Joksimovic and Bohn 2013GLAVASKI-JOKSIMOVIC A AND BOHN MC. 2013. Mesenchymal stem cells and neuroregeneration in Parkinson's disease. Exp Neurol 247: 25-38.). Thus, it is clear that new therapeutic strategies are needed to decrease neuronal loss and slow progression of disease.
MSCs therapy has been considered in PD to replace lost neurons in the substantia nigra with healthy dopaminergic neurons and to avoid neuron loss (Huang et al. 2012HUANG B, TABATA Y AND GAO JQ. 2012. Mesenchymal stem cells as therapeutic agents and potential targeted gene delivery vehicle for brain diseases. J Control Release 162: 464-473.). Over the past years, an increasing number of reports have described promising results of MSCs therapy in experimental models of PD. Animals treated with MSCs had the capacity to protect and decrease damage in dopaminergic neurons (Blandini et al. 2010BLANDINI F ET AL. 2010. Transplantation of undifferentiated human mesenchymal stem cells protects against 6-hydroxydopamine neurotoxicity in the rat. Cell Transplant 19: 203-217., Danielyan et al. 2011DANIELYAN L ET AL. 2011. Therapeutic efficacy of intranasally delivered mesenchymal stem cells in a rat model of Parkinson disease. Rejuvenation Res 14: 3-16., Li et al. 2001LI Y, CHEN J, WANG L, ZHANG L, LU M AND CHOPP M. 2001. Intracerebral transplantation of bone marrow stromal cells in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. Neurosci Lett 316: 67-70.).
Improved behavior has been observed in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of PD after bone marrow-derived MSCs transplantation (Li et al. 2001LI Y, CHEN J, WANG L, ZHANG L, LU M AND CHOPP M. 2001. Intracerebral transplantation of bone marrow stromal cells in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. Neurosci Lett 316: 67-70.). In addition, increased viability and migration of transplanted bone marrow-derived MSCs was observed in lost dopaminergic neurons after the administration of 6-hydroxydopamine (6-OHDA) in an animal model (Hellmann et al. 2006HELLMANN MA, PANET H, BARHUM Y, MELAMED E AND OFFEN D. 2006. Increased survival and migration of engrafted mesenchymal bone marrow stem cells in 6-hydroxydopamine-lesioned rodents. Neurosci Lett 395: 124-128.).
MSCs have also been used as a vector for gene delivery in a rat model of PD: cells were transfected with the gene coding for tyrosine hidroxylase (TH), which is the limiting-rate enzyme for dopamine synthesis. The authors reported successful transfer and expression of the TH gene in the rat striatum, as well as clinical improvement (Lu et al. 2005LU L, ZHAO, C, LIU Y, SUN X, DUA C, JI M, ZHAO H, XU Q AND YANG H. 2005. Therapeutic benefit of TH-engineered mesenchymal stem cells for Parkinson's disease. Brain Res Brain Res Protoc 15: 46-51.). Experimental studies have shown that MSCs conditioned medium promotes the survival of grafted xenogeneic dopaminergic neurons in affected mice (Shintani et al. 2007SHINTANI A, NAKAO N, KAKISHITA K AND ITAKURA T. 2007. Protection of dopamine neurons by bone marrow stromal cells. Brain Res 1186: 48-55.). Another study using MSCs intravenously showed a significant decrease in the loss of dopaminergic neurons in rats treated with MG-132, which causes a neurodegenerative disease similar to PD (Park et al. 2008PARK HJ, LEE PH, BANG OY, LEE G AND AHN YH. 2008. Mesenchymal stem cells therapy exerts neuroprotection in a progressive animal model of Parkinson's disease. J Neurochem 107: 141-151.). Furthermore, intravenous injection of MSCs reduced the loss of dopaminergic neurons in models of disease induced by injection of lipopolysaccharide (LPS) into the substantia nigra or by intraperitoneal injection of MPTP (Kim et al. 2009KIM YJ, PARK HJ, LEE G, BANG OY, AHN YH, JOE E, KIM HO AND LEE PH. 2009. Neuroprotective effects of human mesenchymal stem cells on dopaminergic neurons through anti-inflammatory action. Glia 57: 13-23.). In another study, treatment with MSCs and pretreatment with glial cell line-derived neurotrophic factor (GDNF) increased the proportion of TH-positive and dopamine-producing cells, resulting in clinical improvement in a 6-OHDA rat model of PD (Dezawa et al. 2004DEZAWA M ET AL. 2004. Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation. J Clin Invest 113:12 1701-1710.). Yet another study of the same group of authors showed that administration of dopaminergic neuron-like MSCs to the striatum, ameliorated motor function in parkinsonian macaques - a finding that was associated with restoration of the dopaminergic function (Hayashi et al. 2013HAYASHI T ET AL. 2013. Autologous mesenchymal stem cell-derived dopaminergic neurons function in parkinsonian macaques. J Clin Invest 123: 272-284.). Finally, in the same line, intra-striatal injection of MSCs cultured in favorable conditions for neuronal differentiation has been shown to improve clinical symptoms in murine models of PD (Bouchez et al. 2008BOUCHEZ G, SENSEBE L, VOURC'H P, GARREAU L, BODARD S, RICO A, GUILLOTEAU D, CHARBORD P, BESNARD JC AND CHALON S. 2008. Partial recovery of dopaminergic pathway after graft of adult mesenchymal stem cells in a rat model of Parkinson's disease. Neurochem Int 52: 1332-1342., Levy et al. 2008LEVY YS, BAHAT-STROOMZA M, BARZILAY R, BURSHTEIN A, BULVIK S, BARHUM Y, PANET H, MELAMED E AND OFFEN D. 2008. Regenerative effect of neural-induced human mesenchymal stromal cells in rat models of Parkinson's disease. Cytotherapy 10: 340-352.). One of the latter studies found comparable efficacy when using undifferentiated MSCs (Bouchez et al. 2008).
Other mechanisms of action of MSCs in PD refer to the immunomodulatory and anti-inflammatory effects of these cells. There is a body of evidence suggesting that inflammation and microglial proliferation are involved in the pathophysiology of PD. One study has demonstrated that MSCs have the capacity to protect dopaminergic neurons from LPS-induced microglial activation and from the production of nitric oxide and tumor necrosis factor alpha (TNF-α) (Kim et al. 2009KIM YJ, PARK HJ, LEE G, BANG OY, AHN YH, JOE E, KIM HO AND LEE PH. 2009. Neuroprotective effects of human mesenchymal stem cells on dopaminergic neurons through anti-inflammatory action. Glia 57: 13-23.). Chao et al. (2009)CHAO YX, HE BP AND TAY SS. 2009. Mesenchymal stem cell transplantation attenuates blood brain barrier damage and neuroinflammation and protects dopaminergic neurons against MPTP toxicity in the substantia nigra in a model of Parkinson's disease. J Neuroimmunol 216: 39-50. observed that intravenous administration of mouse MSCs, protected dopaminergic neurons from MPTP toxicity and decreased microglial activation (Chao et al. 2009CHAO YX, HE BP AND TAY SS. 2009. Mesenchymal stem cell transplantation attenuates blood brain barrier damage and neuroinflammation and protects dopaminergic neurons against MPTP toxicity in the substantia nigra in a model of Parkinson's disease. J Neuroimmunol 216: 39-50.). Those studies reinforce the potential importance of the immunomodulatory effects of MSCs for the treatment of PD.
In humans, only one clinical trial has been conducted, consisting of seven PD patients aged between 22 and 62 years, followed up for a period that ranged from 10 to 36 months. The patients received a single dose of autologous bone marrow-derived MSCs transplanted to the subventricular zone using stereotaxic surgery. Three of the seven patients showed an improvement in symptoms, with a decrease in off/on periods measured using Unified Parkinson's Disease Rating Scale. Two patients also reported subjective improvement of symptoms and reduction in drug dosage (Venkataramana et al. 2010VENKATARAMANA NK ET AL. 2010. Open-labeled study of unilateral autologous bone-marrow-derived mesenchymal stem cell transplantation in Parkinson's disease. Transl Res 155: 62-70.). Further investigation is necessary to confirm the efficacy of this therapy.
MULTIPLE SCLEROSIS
Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease that affects the CNS, characterized by recurrent episodes of axonal lesion and demyelination (Compston and Coles 2002COMPSTON A AND COLES A. 2002. Multiple sclerosis. Lancet 359: 1221-1231., Hernandez-Pedro et al. 2013HERNANDEZ-PEDRO NY, ESPINOSA-RAMIREZ G, DE LA CRUZ VP, PINEDA B AND SOTELO J. 2013. Initial Immunopathogenesis of Multiple Sclerosis: Innate Immune Response. Clin Dev Immunol 413-465.). MS is the most common cause of neurological disability in young adults (Chandran et al. 2008CHANDRAN S, HUNT D, JOANNIDES A, ZHAO C, COMPSTON A AND FRANKLIN RJ. 2008. Myelin repair: the role of stem and precursor cells in multiple sclerosis. Philos Trans R Soc Lond B Biol Sci 363: 171-183.). Treatments currently available focus on the immune system, aiming to control the inflammatory process that leads to demyelination (Karussis and Kassis 2008KARUSSIS D ET AL. 2010. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol 67: 1187-1194.). These therapies are only partially effective, as they are not capable of reversing neuronal damage. Because neurodegeneration is thought to be the cause of the gradual worsening observed in patients with MS, new approaches that promote neuronal repair are needed (Cohen 2013COHEN JA. 2013. Mesenchymal stem cell transplantation in multiple sclerosis. J Neurol Sci 333: 43-49.).
Over the last decade, several preclinical studies have demonstrated a great potential of MSCs in the treatment of MS (Gerdoni et al. 2007GERDONI E ET AL. 2007. Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis. Ann Neurol 61: 219-227., Karussis et al. 2010, Zappia et al. 2005ZAPPIA E ET AL. 2005. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 106: 1755-1761., Zhang et al. 2005ZHANG J, LI Y, CHEN J, CUI Y, LU M, ELIAS SB, MITCHELL JB, HAMMILL L, VANGURI P AND CHOPP M. 2005. Human bone marrow stromal cell treatment improves neurological functional recovery in EAE mice. Exp Neurol 195: 16-26.). The most common animal model of MS is experimental autoimmune encephalomyelitis (EAE), in which immunization with neural antigens derived mainly from myelin, in combination with adjuvants, leads to demyelination, inflammation, and axonal damage in the CNS (Cohen 2013COHEN JA. 2013. Mesenchymal stem cell transplantation in multiple sclerosis. J Neurol Sci 333: 43-49.). Zappia et al. (2005)ZAPPIA E ET AL. 2005. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 106: 1755-1761. have shown that intravenous injection of MSCs in mice with chronic EAE leads to reduction of demyelination and CNS infiltration by inflammatory cells (Zappia et al. 2005ZAPPIA E ET AL. 2005. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 106: 1755-1761.). In that study, MSCs also improved the clinical severity of MS. MSCs were effective when administered at disease onset and peak, but not after disease stabilization. In a study conducted by Zhang et al. (2005)ZHANG J, LI Y, CHEN J, CUI Y, LU M, ELIAS SB, MITCHELL JB, HAMMILL L, VANGURI P AND CHOPP M. 2005. Human bone marrow stromal cell treatment improves neurological functional recovery in EAE mice. Exp Neurol 195: 16-26., MSCs also caused significant functional improvement when injected intravenously in EAE mice, with some level of engraftment in the CNS. Demyelination significantly decreased, and BDNF cells significantly increased in treated mice, compared to controls (Zhang et al. 2005ZHANG J, LI Y, CHEN J, CUI Y, LU M, ELIAS SB, MITCHELL JB, HAMMILL L, VANGURI P AND CHOPP M. 2005. Human bone marrow stromal cell treatment improves neurological functional recovery in EAE mice. Exp Neurol 195: 16-26.).
The immunomodulatory activity of MSCs is relevant for the treatment of MS, but it is important to keep in mind that the effects of MSCs are not limited to these properties. MSCs have been shown protect neurons even with very limited evidence of engraftment or transdifferentiation (Morando et al. 2012MORANDO S, VIGO T, ESPOSITO M, CASAZZA S, NOVI G, PRINCIPATO MC, FURLAN R AND UCCELLI A. 2012. The therapeutic effect of mesenchymal stem cell transplantation in experimental autoimmune encephalomyelitis is mediated by peripheral and central mechanisms. Stem Cell Res Ther 3: 3.). MSCs can inhibit pathogenic myelin-specific antibodies, as shown in the study by Gerdoni et al. (2007)GERDONI E ET AL. 2007. Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis. Ann Neurol 61: 219-227., where a limited number of labeled MSCs were detected in the CNS of treated EAE mice (Bai et al. 2009BAI L, LENNON DP, EATON V, MAIER K, CAPLAN AI, MILLER SD AND MILLER RH. 2009. Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis. Glia 57: 1192-1203., Gerdoni et al. 2007GERDONI E ET AL. 2007. Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis. Ann Neurol 61: 219-227.). Many other studies have demonstrated that these cells can modulate peripheral immune response to myelin antigens. Bai et al. (2009)BAI L, LENNON DP, EATON V, MAIER K, CAPLAN AI, MILLER SD AND MILLER RH. 2009. Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis. Glia 57: 1192-1203. showed that treatment with human bone marrow-derived MSCs, reduced inflammatory T-cells and associated cytokines, and concomitantly increased IL-4-producing type 2 helper (Th2) cells and anti-inflammatory cytokines in treated EAE mice (Bai et al. 2009BAI L, LENNON DP, EATON V, MAIER K, CAPLAN AI, MILLER SD AND MILLER RH. 2009. Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis. Glia 57: 1192-1203.).
Based on the evidence provided by preclinical studies, a few clinical trials have attempted to demonstrate the safety and efficacy of MSCs in patients with MS (Bonab et al. 2012BONAB MM ET AL. 2012. Autologous mesenchymal stem cell therapy in progressive multiple sclerosis: an open label study. Curr Stem Cell Res Ther 7: 407-414., Connick et al. 2012CONNICK P ET AL. 2012. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol 11: 150-156., Karussis et al. 2010KARUSSIS D ET AL. 2010. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol 67: 1187-1194., Yamout et al. 2010YAMOUT B ET AL. 2010. Bone marrow mesenchymal stem cell transplantation in patients with multiple sclerosis: a pilot study. J Neuroimmunol 227: 185-189.). All those studies were open-label and employed autologous MSCs. Bonab et al. (2012)BONAB MM ET AL. 2012. Autologous mesenchymal stem cell therapy in progressive multiple sclerosis: an open label study. Curr Stem Cell Res Ther 7: 407-414. studied 25 patients with progressive MS unresponsive to conventional treatment recruited to receive a single intrathecal injection of autologous bone marrow-derived MSCs. Therapeutic response was followed for 12 months, and the authors showed that the clinical course of the disease could be stabilized with no serious adverse effects (Bonab et al. 2012BONAB MM ET AL. 2012. Autologous mesenchymal stem cell therapy in progressive multiple sclerosis: an open label study. Curr Stem Cell Res Ther 7: 407-414.). Another recent clinical trial assessed the neuroprotective effects of intravenous MSCs on optic nerve function and reported improvement after MSCs injection (Connick et al. 2012CONNICK P ET AL. 2012. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol 11: 150-156.).
Currently, there are a upcoming clinical trials registered in clinicaltrials.gov aiming to assess the efficacy of MSCs therapies in MS. Although this approach has shown promising results, larger randomized controlled clinical trials are needed to determine treatment feasibility and to elucidate the mechanisms by which this tool can be useful.
HUNTINGTON'S DISEASE
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutation in the huntingtin (htt) gene. HD is characterized by neuronal cell loss leading to intellectual decline, movement disorders, and behavioral changes (Lin et al. 2011LIN YT, CHERN Y, SHEN CK, WEN HL, CHANG YC, LI H, CHENG TH AND HSIEH-LI HM. 2011. Human mesenchymal stem cells prolong survival and ameliorate motor deficit through trophic support in Huntington's disease mouse models. PLoS One 6: e22924., Maucksch et al. 2013MAUCKSCH C, VAZEY EM, GORDON RJ AND CONNOR B. 2013. Stem cell-based therapy for Huntington's disease. J Cell Biochem 114: 754-763.). The neuropathology of HD manifests in the progressive degeneration of striatal GABAergic neurons. Currently, there is no therapy available capable of interrupting disease progression (Lin et al. 2011LIN YT, CHERN Y, SHEN CK, WEN HL, CHANG YC, LI H, CHENG TH AND HSIEH-LI HM. 2011. Human mesenchymal stem cells prolong survival and ameliorate motor deficit through trophic support in Huntington's disease mouse models. PLoS One 6: e22924., Maucksch et al. 2013MAUCKSCH C, VAZEY EM, GORDON RJ AND CONNOR B. 2013. Stem cell-based therapy for Huntington's disease. J Cell Biochem 114: 754-763.).
There is a large interest in the use of MSCs to treat HD, and several preclinical studies have investigated the potential applications of this therapy in animal models. Lee et al. (2009b)LEE ST ET AL. 2009b. Slowed progression in models of Huntington disease by adipose stem cell transplantation. Ann Neurol 66: 671-681. showed that human adipose-derived MSCs transplanted into the ipsilateral striatal border of mice transgenic for HD, increased survival, attenuated the loss of striatal neurons, and reduced htt aggregates (Lee et al. 2009bLEE ST ET AL. 2009b. Slowed progression in models of Huntington disease by adipose stem cell transplantation. Ann Neurol 66: 671-681.). The same study also investigated the effects of human adipose-derived MSCs in cell culture. The authors demonstrated that the cells secreted multiple growth factors, e.g., BDNF, IGF-1, and NGF, among others.
A recent study investigated the effect of the extract of adipose-derived MSCs in a HD mouse model and in neuronal cells. Intraperitoneal injection of the extract improved performance in the rotarod test, used to evaluate motor coordination in rodents and especially sensitive to detect cerebellar dysfunction (Im et al. 2013IM W, BAN J, LIM J, LEE M, LEE ST, CHU K AND KIM M. 2013. Extracts of adipose derived stem cells slows progression in the R6/2 model of Huntington's disease. PLoS One 8: e59438., Shiotsuki et al. 2010SHIOTSUKI H, YOSHIMI K, SHIMO Y, FUNAYAMA M, TAKAMATSU Y, IKEDA K, TAKAHASHI R, KITAZAWA S AND HATTORI N. 2010. A rotarod test for evaluation of motor skill learning. J Neurosci Methods 189: 180-185.) . Treatment also ameliorated atrophy and mutant httaggregation in the striatum. Neuro2A neuroblastoma cells treated with the same extract showed increased expression of cAMP response element-binding protein (p-CREB) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC1α), which could modify HD progression (Im et al. 2013IM W, BAN J, LIM J, LEE M, LEE ST, CHU K AND KIM M. 2013. Extracts of adipose derived stem cells slows progression in the R6/2 model of Huntington's disease. PLoS One 8: e59438.).
Another two studies have investigated the effects of human MSCs in different mouse models of HD (Lin et al. 2011, Snyder et al. 2010SNYDER BR, CHIU AM, PROCKOP DJ AND CHAN AW. 2010. Human multipotent stromal cells (MSCs) increase neurogenesis and decrease atrophy of the striatum in a transgenic mouse model for Huntington's disease. PLoS One 5: e9347.). Both studies demonstrated reduced striatal atrophy after intrastriatal transplantation of human MSCs, suggesting a neuroprotective effect associated with the neurotrophic factors secreted by these cells (Maucksch et al. 2013MAUCKSCH C, VAZEY EM, GORDON RJ AND CONNOR B. 2013. Stem cell-based therapy for Huntington's disease. J Cell Biochem 114: 754-763.).
Results reported in studies with animal models are encouraging. However, further studies are required, especially clinical trials, to establish the safety and effectiveness of using MSCs in the treatment of HD.
MSCs APPLICATION IN PSYCHIATRIC DISORDERS
Over the past few years, many studies have focused on immunological abnormalities and the decrease of neurotrophic factors that characterize the pathophysiology of psychiatric disorders. Several studies have shown increased levels of pro-inflammatory cytokines, e.g., TNF-α, IL-6, and IL-2, as well as decreased levels of BDNF, an important neurotrophin for CNS, in severe mental illnesses, such as bipolar disorder, schizophrenia, and major depression (Asevedo et al. 2013ASEVEDO E ET AL. 2013. Impact of peripheral levels of chemokines, BDNF and oxidative markers on cognition in individuals with schizophrenia. J Psychiatr Res 7: 1376-1382., Kapczinski et al. 2011KAPCZINSKI F ET AL. 2011. Peripheral biomarkers and illness activity in bipolar disorder. J Psychiatr Res 45: 156-161., Kunz et al. 2011KUNZ M ET AL. 2011. Serum levels of IL-6, IL-10 and TNF-alpha in patients with bipolar disorder and schizophrenia: differences in pro- and anti-inflammatory balance. Rev Bras Psiquiatr 33: 268-74., Patas et al. 2013PATAS K, PENNINX BW, BUS BA, VOGELZANGS N, MOLENDIJK ML, ELZINGA BM, BOSKER FJ AND OUDE VOSHAAR RC. 2013. Association between serum brain-derived neurotrophic factor and plasma interleukin-6 in major depressive disorder with melancholic features. Brain Behav Immun 36: 71-79.). Furthermore, many studies have shown important cognitive impairment, neuroanatomical alterations and decreased neurogenesis in the hippocampus of patients with affective disorders (Caletti et al. 2013CALETTI E ET AL. 2013. Neuropsychology, social cognition and global functioning among bipolar, schizophrenic patients and healthy controls: preliminary data. Front Hum Neurosci 7: 661., Dranovsky and Hen 2006DRANOVSKY A AND HEN R. 2006. Hippocampal neurogenesis: regulation by stress and antidepressants. Biol Psychiatry 59: 1136-1143., Thomas et al. 2007THOMAS RM, HOTSENPILLER G AND PETERSON DA. 2007. Acute psychosocial stress reduces cell survival in adult hippocampal neurogenesis without altering proliferation. J Neurosci 27: 2734-2743., Torrent et al. 2010TORRENT C ET AL. 2010. Long-term outcome of cognitive impairment in bipolar disorder. J Clin Psychiatry 73: e899-905., Trivedi and Greer 2013TRIVEDI MH AND GREER TL. 2013. Cognitive dysfunction in unipolar depression: Implications for treatment. J Affect Disord 152: 19-27.).
In fact, despite the promising contributions of MSCs therapies in psychiatry, few studies have evaluated the effects of MSCs in models of psychiatric disorders. MSCs have the ability to promote neurogenesis and the survival and differentiation of neural cells by expressing neurotrophic factors, e.g., BDNF, NGF, and IGF. Moreover, as a result of their immunomodulatory properties, they can prevent apoptosis and decrease inflammation (Crigler et al. 2006CRIGLER L, ROBEY RC, ASAWACHAICHARN A, GAUPP D AND PHINNEY DG. 2006. Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis. Exp Neurol 198: 54-64., Yoo et al. 2008YOO SW, KIM SS, LEE SY, LEE HS, KIM HS, LEE YD AND SUH-KIM H. 2008. Mesenchymal stem cells promote proliferation of endogenous neural stem cells and survival of newborn cells in a rat stroke model. Exp Mol Med 40: 387-397.).
Tfilin et al. (2010)TFILIN M, SUDAI E, MERENLENDER A, GISPAN I, YADID G AND TURGEMAN G. 2010. Mesenchymal stem cells increase hippocampal neurogenesis and counteract depressive-like behavior. Mol Psychiatry 15: 1164-1175. showed that treatment of an animal model of depression with MSCs, increased hippocampal neurogenesis and improved depressive behavior (Tfilin et al. 2010TFILIN M, SUDAI E, MERENLENDER A, GISPAN I, YADID G AND TURGEMAN G. 2010. Mesenchymal stem cells increase hippocampal neurogenesis and counteract depressive-like behavior. Mol Psychiatry 15: 1164-1175.). Another study evidenced that intra-hippocampal transplantation of MSCs enhanced neurogenesis and did not impair behavioral functions in rats (Coquery et al. 2012COQUERY N, BLESCH A, STROH A, FERNANDEZ-KLETT F, KLEIN J, WINTER C AND PRILLER J. 2012. Intrahippocampal transplantation of mesenchymal stromal cells promotes neuroplasticity. Cytotherapy 14: 1041-1053.). These results are promising and may lead to a novel modality for the treatment of psychiatric disorders. However, more studies are necessary to elucidate the precise mechanisms of action of MSCs in mental illness.
CONCLUSIONS
There are numerous preclinical studies using MSCs transplantation for diseases on the CNS that show promising results. These studies suggest that MSCs act through release of different neurotrophic factors, anti-inflammatories and antiapoptotic factors that can promote recover the injured area and prevent damage in neurodegenerative disorder. However, more clinical studies are necessary to understand the exact mechanism of action of MSCs in neurodegenerative disease and evaluate if the treatment with MSCs could cause side effects in patients. On the other hands, there are a few studies using the MSCs in psychiatric disease, but these studies have demonstrated promising results in depression and suggest that the MSCs can be a new strategy for the treatment of mental disorder. Future studies should be developed to evaluate the most effective routes of administration, dose and source of MSCs for each disease and their therapeutics effects. Thus, this new treatment may became an important therapeutic option for psychiatric patientes that do not respond to conventional treatment.
ACKNOWLEDGMENTS
F Kapczinski has received grant/research support from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), NARSAD and the Stanley Medical Research Institute; he has been a member of the speakers' boards for Astra-Zeneca, Eli Lilly, Janssen and Servier; and has served as a consultant for Servier. EO Cirne-Lima, J Quevedo and AR Rosa have grants from CNPq-INCT-TM, and FIPE-HCPA. GD Colpo, BM Ascoli, BW Aguiar, B Pffafenseller, EG da Silva have schoorship from CNPq and CAPES.
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Publication Dates
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Publication in this collection
04 Aug 2015 -
Date of issue
Aug 2015
History
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Received
11 Dec 2014 -
Accepted
13 May 2015