{"paper_id":"cf19e3e3-1768-4ec1-9796-4a8f4d01cee5","body_text":"Mesenchymal Stem/Stromal Cell Dysfunction as an Early Pathological Feature of Parkinson's Disease: Implications for Allogeneic Cell Therapy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Mesenchymal Stem/Stromal Cell Dysfunction as an Early Pathological Feature of Parkinson's Disease: Implications for Allogeneic Cell Therapy Rituparna Ghanty, Kallolika Mondal, Nitish Kamble, Ravi Yadav, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8572991/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract PD is associated with marked heterogeneity in immune signatures, indicating that therapeutic strategies targeting individual immune cell populations are unlikely to be broadly effective and instead reflect a failure of upstream systemic immunoregulation. While bone marrow–derived mesenchymal stem/stromal cells (BMMSCs) are critical regulators of immune homeostasis and regenerative responses, their functional status during PD progression has not been investigated. Using a combination of MPTP-induced rat chronic PD model, patient-derived induced pluripotent stem cell (iPSC), and in vitro and in vivo transplantation paradigms, we examined MSC function across disease stages. We assessed MSC proliferation, survival, migration, differentiation, oxidative stress, and immunomodulatory capacity, and evaluated their impact on neuroinflammation, dopaminergic-neurodegeneration, neurogenesis, and motor-function. We identify early and progressive MSC dysfunction, emerging during the pre-motor stage and preceding motor deficits. In MPTP-treated rats, bone marrow–derived MSC impairment coincided with early dopaminergic-neuron loss, microglial-activation, and elevated TNF-α & NLRP3 levels. Patient-derived sporadic PD-iMSCs recapitulated these defects, exhibiting reduced proliferation and survival, impaired migration, elevated oxidative stress, diminished differentiation potential, and—most critically—profound loss of immunomodulatory capacity. Autologous PD-iMSCs failed to suppress hyperactivated patient immune cells and showed reduced therapeutic efficacy in vivo, whereas healthy donor-derived iMSCs robustly attenuated peripheral and neuroinflammation, enhanced dopaminergic-neurons, promoted substantia-nigra neurogenesis, and improved motor outcomes. These findings indicate that peripheral MSC integrity critically determines CNS inflammatory tone and regenerative capacity, revealing MSC dysfunction as a systemic driver of neurodegeneration rather than a secondary consequence of PD. It also highlights the strong translational rationale for prioritizing allogeneic MSC-based therapeutic strategies in PD. Biological sciences/Cell biology Biological sciences/Immunology Health sciences/Neurology Biological sciences/Neuroscience Biological sciences/Stem cells Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 13 Feb, 2026 Reviews received at journal 13 Feb, 2026 Reviews received at journal 10 Feb, 2026 Reviews received at journal 10 Feb, 2026 Reviewers agreed at journal 22 Jan, 2026 Reviewers agreed at journal 20 Jan, 2026 Reviewers agreed at journal 15 Jan, 2026 Reviewers invited by journal 15 Jan, 2026 Editor assigned by journal 14 Jan, 2026 Submission checks completed at journal 14 Jan, 2026 First submitted to journal 11 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-8572991\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Article\",\"associatedPublications\":[],\"authors\":[{\"id\":576004913,\"identity\":\"78c2f25c-7e8e-4590-afdb-7e6f96615c72\",\"order_by\":0,\"name\":\"Rituparna Ghanty\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"National Institute of Mental Health and Neurosciences\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Rituparna\",\"middleName\":\"\",\"lastName\":\"Ghanty\",\"suffix\":\"\"},{\"id\":576004914,\"identity\":\"52980561-f4db-45f3-af62-1e0ec4f0d633\",\"order_by\":1,\"name\":\"Kallolika 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