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Treatment of a genetic brain disease by CNS-wide microglia replacement
Open accessAbstract
Hematopoietic cell transplantation after myeloablative conditioning has been used to treat various genetic metabolic syndromes but is largely ineffective in diseases affecting the brain presumably due to poor and variable myeloid cell incorporation into the central nervous system. Here, we developed and characterized a near-complete and homogeneous replacement of microglia with bone marrow cells in mice without the need for genetic manipulation of donor or host. The high chimerism resulted from a competitive advantage of scarce donor cells during microglia repopulation rather than enhanced recruitment from the periphery. Hematopoietic stem cells, but not immediate myeloid or monocyte progenitor cells, contained full microglia replacement potency equivalent to whole bone marrow. To explore its therapeutic potential, we applied microglia replacement to a mouse model for Prosaposin deficiency, which is characterized by a progressive neurodegeneration phenotype. We found a reduction of cerebellar neurodegeneration and gliosis in treated brains, improvement of motor and balance impairment, and life span extension even with treatment started in young adulthood. This proof-of-concept study suggests that efficient microglia replacement may have therapeutic efficacy for a variety of neurological diseases.
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TL;DR
A busulfan-based bone marrow transplant followed by transient CSF1R inhibition (PLX5622) achieved near-complete, homogeneous microglia replacement by circulation-derived myeloid cells (CDMCs) in mice without genetic manipulation of donor or host. In a Prosaposin-deficiency neurodegeneration model, this microglia replacement reduced cerebellar pathology, improved motor/balance deficits, and extended lifespan even when started in young adulthood.
Key findings
- Conventional BMT alone gave slow, variable brain chimerism (7.1–73.4%) that plateaued by 12 weeks and did not significantly increase by 24 weeks (p=0.99); adding PLX5622 four weeks after BMT yielded >90% GFP+ donor cells among brain myeloid cells by flow cytometry, stable for at least 6 months.
- CDMCs were transcriptionally distinct from microglia: RNA-seq found 1296 differentially expressed genes (log2FC > 1, FDR < 0.05; 564 microglia, 732 CDMCs), and CDMCs showed DAM-like gene expression; TMEM119 expression was lower in CDMCs than microglia after BMT only (48.3% vs 87.6%, p < 0.001) but increased after BMT+PLX5622.
- Purified hematopoietic stem cells (HSCs) had the highest brain engraftment capacity: HSC-derived CDMCs reached 10–40% brain myeloid chimerism at 4 weeks and nearly outcompeted helper whole bone marrow after PLX5622, unlike CMPs, bone marrow monocytes, or whole bone marrow controls.
- In the Prosaposin-deficiency model, treatment at ~8–9 weeks reduced total cerebellar GC species (p < 0.05), increased surviving calbindin-positive Purkinje cells, reduced astrogliosis, improved beam-walk performance (p < 0.001), and extended survival: PSAPHigh→PSAPLow mice survived 19.3% longer than untreated PSAPLow mice (p=0.01), while PSAPLow→PSAPLow mice trended 7.4% longer.
Methods
- Mice were C57BL/6 females at 8–12 weeks unless noted. BMT used busulfan conditioning (25 mg/kg IP daily for 5 days), 5×10^6 bone marrow cells injected retro-orbitally, and PLX5622 diet (1200 PPM) before and/or for 10 days starting day 28 after BMT.
- Characterization included flow cytometry, histology/morphometry, FACS-purified RNA-seq, qPCR, ex vivo phagocytosis, two-photon live imaging, LPS-induced cytokine multiplex assay, Y-maze, and behavioral/survival testing in the Prosaposin model.
- Statistical analyses used unpaired two-tailed Student’s t tests, one-sample t tests, one-way ANOVA with post hoc tests, and log-rank tests for survival; behavior and morphology were blinded, and mice were randomized to treatment groups.
Limitations
- The paper states that long-term effects of microglia replacement are not well understood, CDMCs may respond differently to CNS pathology than microglia, and BMT has severe side effects including immunosuppression and chemotherapy-associated toxicity, limiting current applicability to aggressive life-threatening diseases.
- The authors state the treatment was not a cure and effects were partial; PSAP protein was not restored to PSAPHigh levels, and secreted PSAP from CDMCs was lower than from microglia.
- Evident from the text: the therapeutic proof-of-concept is in a single mouse model, no conventional BMT control was included in the therapeutic arm because of variable brain chimerism, and human translation remains untested.
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“Using HSCs as donor cells has some practical advantages as they are well defined, can be expanded in culture by several hundred-fold (56) and genetically manipulated by efficient lentiviral gene transfer allowing the ex vivo genetic engineering of donor cells to bestow transplanted cells with additional therapeutic properties.”
§ Treatment of a genetic brain disease by CNS-wide microglia replacement > Discussion
What the sources say
- Supportedcites [56] Wilkinson AC, Ishida R, Kikuchi M, Sudo K, Morita M, Crisostomo RV, Yamamoto R, Loh KM, Nakamura Y, Watanabe M, Nakauchi H, Yamazaki S, Long-term ex vivo haematopoietic-stem-cell expansion allows nonconditioned transplantation. Nature. 571, 117– 121 (2019). 31142833 PMC7006049 source
The main text reports that, under optimized culture conditions, functional mouse HSCs expanded an estimated 236- to 899-fold over 28 days. That supports the cited claim that HSCs can be expanded in culture by several hundred-fold. (LLM, conf=0.94)
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In the paper
“Of note, the degree of brain chimerism was highly variable between mice ranging from 7.1–73.4% (Fig. 1C).”
§ Treatment of a genetic brain disease by CNS-wide microglia replacement > Results > Microglia replacement following BMT is slow, inefficient and highly variable
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In the paper
“In the same time frame, intravenously injected donor cells did not display similar microglial differentiation following BMT (Fig.1, D and E).”
§ Treatment of a genetic brain disease by CNS-wide microglia replacement > Results > Microglia replacement following BMT is slow, inefficient and highly variable
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In the paper
“As seen in native mice (27), PLX5622 treatment after BMT had no major effects on various monocyte populations in the peripheral blood (fig. S1, D and E).”
§ Treatment of a genetic brain disease by CNS-wide microglia replacement > Results > Microglia depletion after BMT results in near complete replacement of microglia with CDMCs throughout the entire brain
What the sources say
- Not checked yetcites [27] Valdearcos M, Douglass JD, Robblee MM, Dorfman MD, Stifler DR, Bennett ML, Gerritse I, Fasnacht R, Barres BA, Thaler JP, Koliwad SK, Microglial Inflammatory Signaling Orchestrates the Hypothalamic Immune Response to Dietary Excess and Mediates Obesity Susceptibility. Cell Metabolism. 26, 185–197.e3 (2017). PMC5569901 28683286 source
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In the paper
“Here, we developed and characterized a near-complete and homogeneous replacement of microglia with bone marrow cells in mice without the need of genetic manipulation of donor or host.”
§ Treatment of a genetic brain disease by CNS-wide microglia replacement > Abstract
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Metadata
- Authors
- Shibuya, Y., Kumar, K. K., Mader, M. M.-D., Yoo, Y., Ayala, L. A., Zhou, M., Mohr, M. A., Neumayer, G., Kumar, I., Yamamoto, R., Marcoux, P., Liou, B., Bennett, F. C., Nakauchi, H., Sun, Y., Chen, X., Heppner, F. L., Wyss-Coray, T., Südhof, T. C., & Wernig, M.
- Affiliations
- Stanford Medicine (US)
- Stanford University (US)
- Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
- Cincinnati Children's Hospital Medical Center (US)
- University of Pennsylvania (US)
- German Center for Neurodegenerative Diseases (DE)
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
- Howard Hughes Medical Institute (US)
- Corresponding author
- Kumar, Kevin K.
- Mader, Marius Marc-Daniel
- Yoo, Yongjin
- Wernig, Marius
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2022-03-16
- Volume
- 14
- Issue
- 636
- Pages
- eabl9945-eabl9945
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC9618306
- OpenAlex
- W4221042077
- Cited by
- 126
- References
- 69
- Citations by year
- 2026: 24 · 2025: 38 · 2024: 27 · 2023: 25 · 2022: 12
- FWCI
- 9.84
- Type
- journal article
- Language
- en
- Open access
- green
- pmc.ncbi.nlm.nih.gov
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DZNE Pub (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute on Aging (P50AG047366, P30AG066515)
- National Institute of General Medical Sciences (R25GM059298)
- National Institute of Neurological Disorders and Stroke (P30NS069375, R25NS065741)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
- Keywords
- hematopoietic stem cell transplantation, bone marrow chimerism, hematopoietic stem cells, neurodegeneration, gliosis, cerebellum, motor impairment, lifespan extension, myeloablative conditioning
- MeSH terms
- Animals, Bone Marrow Cells, Brain, Brain Diseases, Central Nervous System, Microglia, Hematopoietic Stem Cell Transplantation, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-12, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-12 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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