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Depletion of harmful microglia and repopulation with healthy progenitors represents a new therapeutic option for neurodegenerative diseases with an urgent need for effective treatments. However, repopulation with patient-derived progenitors could result in similar dysfunction over time. We therefore propose obtaining microglia-like cells (MLCs) derived from healthy donors for allogeneic transplantation. We hypothesize that the immunosuppressive phenotype of MLCs, combined with the brain\u00b4s high immune tolerance, would enable effective engraftment. Additionally, the allogeneic origin of MLCs may increase immune tolerance, with additional therapeutic outcomes, particularly in multiple sclerosis (MS).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      MLCs were generated from MHC-mismatched mouse strains in vitro and exposed to IL-10\/IL-4\/TGF-\u03b2 or LPS\/IFN-\u03b3 to induce specific immunophenotypes. Phagocytosis and T cell proliferation assays assessed MLC responses to pathogenic insults that could arise in autoimmune contexts. Microglial depletion was achieved using Cx3cr1\n                      <jats:sup>CreER\/\u2212<\/jats:sup>\n                      R26\n                      <jats:sup>DTA\/\u2212<\/jats:sup>\n                      mice or PLX3397 treatment. A protocol administering MLCs directly into the brain via the intracisterna magna was optimized to facilitate repopulation of the microglial niche. Repopulation with MHC-mismatched IL-10\/IL-4\/TGF-\u03b2-polarized MLCs was tested in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, with immune profiling of cellular populations conducted using flow cytometry.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>BALB\/c- and C3H-derived MLCs developed more pronounced anti-inflammatory profiles than did C57BL\/6 MLCs, and promoted tolerogenic phenotypes when encountering MHC-mismatched C57BL\/6 T cells. In vivo experiments demonstrated a partial repopulation of an emptied microglia-niche by pre-differentiated MLCs administered intracisternally (i.c) into the CNS. The adoptive transfer of MHC-mismatched MLCs led to enhanced immune tolerance mechanisms and the amelioration of disease progression in the EAE mouse model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings support the therapeutic potential of anti-inflammatory MHC-mismatched MLCs in promoting immune tolerance within autoimmune neuropathologies. Specifically, disease progression was attenuated and tolerogenic mechanisms were activated in the MS mouse model. While a polarization protocol towards an anti-inflammatory phenotype confers MLCs with beneficial features in a pro-inflammatory disease context, the MHC-mismatch interaction within the host\u00b4s CNS promotes additional tolerogenic processes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12974-025-03672-4","type":"journal-article","created":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T00:36:07Z","timestamp":1767832567000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Allogeneic MHC-mismatched microglia-like cell replacement as a therapeutic approach for multiple sclerosis"],"prefix":"10.1186","volume":"23","author":[{"given":"Irene","family":"Benito-Cuesta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Hong","family":"Min","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxi","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia Adriana","family":"Virgilio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Suerth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Bencina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Trigo-Alonso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keying","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin-Yu","family":"Kung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Majid","family":"Pahlevan Kakhki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heela","family":"Sarlus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Harris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,8]]},"reference":[{"issue":"11","key":"3672_CR1","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1016\/j.tins.2019.09.004","volume":"42","author":"A Sierra","year":"2019","unstructured":"Sierra A, Paolicelli RC, Kettenmann H. 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