# Mesenchymal stem cells and the central nervous system: historical perspectives and future directions **Authors:** Christopher Y. Mazurek, Julia K. Kaniuk, Christopher S. Ahuja PMC · DOI: 10.3389/fnmol.2026.1742864 · Frontiers in Molecular Neuroscience · 2026-02-23 ## TL;DR This review explores how mesenchymal stem cells may help treat central nervous system diseases like Alzheimer's and Parkinson's by reducing inflammation and promoting repair. ## Contribution The paper provides a comprehensive overview of MSC therapeutic mechanisms and clinical progress in CNS disorders. ## Key findings - MSCs promote repair through secreted factors that modulate inflammation and immune responses. - MSC secretome and exosomes are increasingly used in clinical trials for CNS pathologies. - Challenges remain in translating MSC therapies to clinical practice. ## Abstract Mesenchymal stem cells (MSCs) have been studied as a potential therapy for a wide range of conditions for approximately 30 years. MSCs have shown promise in treating pathologies of or affecting the central nervous system (CNS), specifically Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), traumatic brain injury (TBI), degenerative disc disease (DDD), and sepsis/meningitis. The therapeutic benefits of MSCs derive primarily from their arsenal of secreted factors that promote anti-inflammatory and pro-survival pathways while attenuating harmful immune responses, thus making them powerful immunomodulatory entities which are also capable of affecting a diverse range of cellular functions to promote endogenous mechanisms of repair. This review summarizes the current state of clinical trials research regarding pathologies of the CNS with a focus on historical progression and upcoming trials. We take a mechanistic approach to explain the therapeutic basis of MSCs and how this has informed clinical trials. We also mention the role of the MSC secretome and MSC exosomes in the treatment of CNS pathologies as well as their increasing use in clinical trials. Finally, we address the challenges inherent to the clinical translation and implementation of MSC therapies along with future directions of the field. ## Linked entities - **Diseases:** Alzheimer’s disease (MONDO:0004975), Parkinson’s disease (MONDO:0005180), amyotrophic lateral sclerosis (MONDO:0004976), multiple sclerosis (MONDO:0005301), stroke (MONDO:0005098), spinal cord injury (MONDO:0043797), traumatic brain injury (MONDO:0858950), degenerative disc disease (MONDO:0044339) ## Full-text entities - **Genes:** PRKAA1 (protein kinase AMP-activated catalytic subunit alpha 1) [NCBI Gene 5562] {aka AMPK, AMPK alpha 1, AMPKa1}, ACAN (aggrecan) [NCBI Gene 176] {aka AGC1, AGCAN, CSPG1, CSPGCP, MSK16, SEDK}, NTF3 (neurotrophin 3) [NCBI Gene 4908] {aka HDNF, NGF-2, NGF2, NT-3, NT3}, CD8A (CD8 subunit alpha) [NCBI Gene 925] {aka CD8, CD8alpha, IMD116, Leu2, p32}, CD14 (CD14 molecule) [NCBI Gene 929], IL1RN (interleukin 1 receptor antagonist) [NCBI Gene 3557] {aka CRMO2, DIRA, ICIL-1RA, IL-1RN, IL-1ra, IL-1ra3}, FGF2 (fibroblast growth factor 2) [NCBI Gene 2247] {aka BFGF, FGF-2, FGFB, HBGF-2}, TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040] {aka CAEND1, CED, DPD1, IBDIMDE, LAP, TGF-beta1}, MAOB (monoamine oxidase B) [NCBI Gene 4129], NFE2L2 (NFE2 like bZIP transcription factor 2) [NCBI Gene 4780] {aka IMDDHH, NRF2, Nrf-2}, NLRP1 (NLR family pyrin domain containing 1) [NCBI Gene 22861] {aka AIADK, CARD7, CIDED, CLR17.1, DEFCAP, DEFCAP-L/S}, Il10 (interleukin 10) [NCBI Gene 16153] {aka CSIF, If2a, Il-10}, Gdnf (glial cell line derived neurotrophic factor) [NCBI Gene 14573] {aka ATF}, CSF2 (colony stimulating factor 2) [NCBI Gene 1437] {aka CSF, GMCSF}, SOD1 (superoxide dismutase 1) [NCBI Gene 6647] {aka ALS, ALS1, HEL-S-44, IPOA, SOD, STAHP}, Tnf (tumor necrosis factor) [NCBI Gene 21926] {aka DIF, TNF-a, TNF-alpha, TNFSF2, TNFalpha, Tnfa}, MAPK1 (mitogen-activated protein kinase 1) [NCBI Gene 5594] {aka ERK, ERK-2, ERK2, ERT1, MAPK2, NS13}, IL17A (interleukin 17A) [NCBI Gene 3605] {aka CTLA-8, CTLA8, IL-17, IL-17A, IL17, ILA17}, MIR223 (microRNA 223) [NCBI Gene 407008] {aka MIRN223, miRNA223, mir-223}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, Tgfb1 (transforming growth factor, beta 1) [NCBI Gene 21803] {aka TGF-beta1, TGFbeta1, Tgfb, Tgfb-1}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, NLRP3 (NLR family pyrin domain containing 3) [NCBI Gene 114548] {aka AGTAVPRL, AII, AVP, C1orf7, CIAS1, CLR1.1}, BCL2 (BCL2 apoptosis regulator) [NCBI Gene 596] {aka Bcl-2, PPP1R50}, DHCR24 (24-dehydrocholesterol reductase) [NCBI Gene 1718] {aka DCE, Nbla03646, SELADIN1, seladin-1}, IFNG (interferon gamma) [NCBI Gene 3458] {aka IFG, IFI, IMD69}, CD40LG (CD40 ligand) [NCBI Gene 959] {aka CD154, CD40L, HIGM1, IGM, IMD3, T-BAM}, MIR221 (microRNA 221) [NCBI Gene 407006] {aka MIRN221, miRNA221, mir-221}, Ntf3 (neurotrophin 3) [NCBI Gene 18205] {aka HDNF, NGF-2, Nt3, Ntf-3}, H2-Ab1 (histocompatibility 2, class II antigen A, beta 1) [NCBI Gene 14961] {aka Abeta, H-2Ab, H2-Ab, I-Abeta, IAb, Ia-2}, WNT9A (Wnt family member 9A) [NCBI Gene 7483] {aka WNT14}, WNT5B (Wnt family member 5B) [NCBI Gene 81029], HLA-A (major histocompatibility complex, class I, A) [NCBI Gene 3105] {aka HLAA}, IFNA1 (interferon alpha 1) [NCBI Gene 3439] {aka IFL, IFN, IFN-ALPHA, IFN-alphaD, IFNA13, IFNA@}, IL4 (interleukin 4) [NCBI Gene 3565] {aka BCGF-1, BCGF1, BSF-1, BSF1, IL-4}, Akt1 (Akt serine/threonine kinase 1) [NCBI Gene 11651] {aka Akt, LTR-akt, PKB, PKB/Akt, PKBalpha, Rac}, CD4 (CD4 molecule) [NCBI Gene 920] {aka CD4mut, IMD79, Leu-3, OKT4D, T4}, IL13 (interleukin 13) [NCBI Gene 3596] {aka IL-13, P600}, CD19 (CD19 molecule) [NCBI Gene 930] {aka B4, CVID3}, TARDBP (TAR DNA binding protein) [NCBI Gene 23435] {aka ALS10, TDP-43}, ITGAM (integrin subunit alpha M) [NCBI Gene 3684] {aka CD11B, CR3A, HNA-4, MAC-1, MAC1A, MO1A}, PSEN1 (presenilin 1) [NCBI Gene 5663] {aka ACNINV3, AD3, CMD1U, FAD, PS-1, PS1}, MIR215 (microRNA 215) [NCBI Gene 406997] {aka MIRN215, miRNA215, mir-215}, CAMP (cathelicidin antimicrobial peptide) [NCBI Gene 820] {aka CAP-18, CAP18, CRAMP, FALL-39, FALL39, HSD26}, Fgf21 (fibroblast growth factor 21) [NCBI Gene 56636] {aka Fgf8c}, WNT5A (Wnt family member 5A) [NCBI Gene 7474] {aka hWNT5A}, WNT7A (Wnt family member 7A) [NCBI Gene 7476] {aka SANTOS, Wnt-7a}, Tlr4 (toll-like receptor 4) [NCBI Gene 21898] {aka Lps, Ly87, Ran/M1, Rasl2-8}, HLA-C (major histocompatibility complex, class I, C) [NCBI Gene 3107] {aka D6S204, HLA-JY3, HLAC, HLC-C, MHC, PSORS1}, CCL2 (C-C motif chemokine ligand 2) [NCBI Gene 6347] {aka GDCF-2, HC11, HSMCR30, MCAF, MCP-1, MCP1}, EGR1 (early growth response 1) [NCBI Gene 1958] {aka AT225, G0S30, KROX-24, NGFI-A, TIS8, ZIF-268}, Cxcr4 (C-X-C motif chemokine receptor 4) [NCBI Gene 12767] {aka CD184, CXC-R4, CXCR-4, Cmkar4, LESTR, PB-CKR}, COX2 (cytochrome c oxidase subunit II) [NCBI Gene 4513] {aka COII, MTCO2}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, Vegfa (vascular endothelial growth factor A) [NCBI Gene 22339] {aka L-VEGF, Vegf, Vpf}, CD79A (CD79a molecule) [NCBI Gene 973] {aka IGA, IGAlpha, MB-1, MB1}, IGF1 (insulin like growth factor 1) [NCBI Gene 3479] {aka IGF, IGF-I, IGFI, MGF}, Sod1 (superoxide dismutase 1, soluble) [NCBI Gene 20655] {aka B430204E11Rik, Cu/Zn-SOD, CuZnSOD, Ipo-1, Ipo1, SODC}, Mtor (mechanistic target of rapamycin kinase) [NCBI Gene 56717] {aka 2610315D21Rik, FRAP, FRAP2, Frap1, RAFT1, RAPT1}, Il13 (interleukin 13) [NCBI Gene 16163] {aka Il-13} - **Diseases:** optic neuritis (MESH:D009902), infection (MESH:D007239), cardiovascular injury (MESH:D002318), loss of function (MESH:D006315), bacteremia (MESH:D016470), motor and sensory deficits (MESH:D001289), ischemic stroke (MESH:D002544), loss of sensation (MESH:D006987), kidney stones (MESH:D007669), cytotoxic (MESH:D064420), AIS (MESH:D013734), osteoporosis (MESH:D010024), dizziness (MESH:D004244), Relapse-remitting MS (MESH:D020529), injury of the spine (MESH:D016135), bacterial meningitis (MESH:D016920), astrogliosis (MESH:D005911), ALS (MESH:D000690), dysphagia (MESH:D003680), tumorigenicity (MESH:D002471), lumbar disc degeneration (MESH:C535531), encephalopathy (MESH:D001927), neurologic injury (MESH:D020196), demyelinating disease (MESH:D003711), death (MESH:D003643), immunodeficiency (MESH:D007153), bradykinesia (MESH:D018476), tremors (MESH:D014202), ICH (MESH:D002543), discogenic back pain (MESH:D001416), urinary retention (MESH:D016055), MCA (MESH:D020244), urinary incontinence (MESH:D014549), viral encephalitis (MESH:D018792), septic shock (MESH:D012772), MS (MESH:D009103), Familial disease (MESH:D057180), muscle rigidity (MESH:D009127), necrosis (MESH:D009336), cognitive deficits (MESH:D003072), Coma (MESH:D003128), autoinflammatory nervous system disorders (MESH:D009422), apoptosis (MESH:D065703), Movement Disorder (MESH:D009069), axonal injury (MESH:D001480), lower extremity weakness (MESH:D020335), Sepsis (MESH:D018805), motor (MESH:D000068079), memory loss (MESH:D008569), inflammatory cytokines (MESH:D000080424), Neuronal (MESH:D009410), orthopedic conditions and injuries (MESH:D009140), sporadic disease (MESH:D020821), ASIA (MESH:D013124), infarct (MESH:D007238), annulus fibrosus degeneration (OMIM:614822), DDD (MESH:D055959), depression (MESH:D003866), kidney injury (MESH:D007674), EAE (MESH:D004681) - **Chemicals:** aspartic acid (MESH:D001224), reactive nitrogen species (MESH:D026361), arginine (MESH:D001120), HLCM501 (-), hydrogen peroxide (MESH:D006861), dextran (MESH:D003911), phosphatidylethanolamine (MESH:C483858), dopamine (MESH:D004298), riluzole (MESH:D019782), lysophosphatidylcholines (MESH:D008244), rosuvastatin (MESH:D000068718), calcium (MESH:D002118), paraquat (MESH:D010269), ROS (MESH:D017382), Gadolinium (MESH:D005682), rotenone (MESH:D012402), glutamine (MESH:D005973), steroid (MESH:D013256), MPTP (MESH:D015632), lipids (MESH:D008055), alendronate (MESH:D019386), permethrin (MESH:D026023), rapamycin (MESH:D020123), adenosine (MESH:D000241), oxygen (MESH:D010100), Iron oxide (MESH:C000499), polydopamine (MESH:C568283), Glutamate (MESH:D018698), NO (MESH:D009569), 5'-deoxy-5'-methylthioadenosine (MESH:C008500), ceramide (MESH:D002518), hyaluronic acid (MESH:D006820), tricalcium phosphate (MESH:C018392), phospholipids (MESH:D010743), NaGdF4 (MESH:C000656715), luminal (MESH:D010634), 6-OHDA (MESH:D016627), iron (MESH:D007501) - **Species:** Rattus norvegicus (brown rat, species) [taxon 10116], Homo sapiens (human, species) [taxon 9606], Neisseria meningitidis (species) [taxon 487], Mus musculus (house mouse, species) [taxon 10090], Haemophilus (genus) [taxon 724], Canis lupus familiaris (dog, subspecies) [taxon 9615], Escherichia coli (E. coli, species) [taxon 562], Streptococcus pneumoniae (species) [taxon 1313] - **Mutations:** A to E, G93A, start in 2026, rs1803274 - **Cell lines:** WJ — Homo sapiens (Human), Glioblastoma, Cancer cell line (CVCL_W352) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12968201/full.md ## Figures 2 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12968201/full.md ## References 476 references — full list in the complete paper: https://tomesphere.com/paper/PMC12968201/full.md --- Source: https://tomesphere.com/paper/PMC12968201