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Updated: Jun 23, 2025
Transplantation of Human Induced Pluripotent Stem Cell-Derived Microglia in Immunocompetent Mice Brain via Non-Invasive Transnasal Route
Published on: May 31, 2022
Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy
Jean Paul Chadarevian1, Jonathan Hasselmann2, Alina Lahian1
1Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA.
Abstract:
Microglia replacement strategies are increasingly being considered for the treatment of primary microgliopathies like adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). However, available mouse models fail to recapitulate the diverse neuropathologies and reduced microglia numbers observed in patients. In this study, we generated a xenotolerant mouse model lacking the fms-intronic regulatory element (FIRE) enhancer within Csf1r, which develops nearly all the hallmark pathologies associated with ALSP. Remarkably, transplantation of human induced pluripotent stem cell (iPSC)-derived microglial (iMG) progenitors restores a homeostatic microglial signature and prevents the development of axonal spheroids, white matter abnormalities, reactive astrocytosis, and brain calcifications. Furthermore, transplantation of CRISPR-corrected ALSP-patient-derived iMG reverses pre-existing spheroids, astrogliosis, and calcification pathologies. Together with the accompanying study by Munro and colleagues, our results demonstrate the utility of FIRE mice to model ALSP and provide compelling evidence that iMG transplantation could offer a promising new therapeutic strategy for ALSP and perhaps other microglia-associated neurological disorders.
Insights
Developing a new mouse model for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), this study shows human microglial transplantation can reverse ALSP pathologies. This offers a promising therapeutic avenue for microgliopathies.
Area of Science:
- Neuroscience
- Genetics
- Stem Cell Biology
Background:
- Primary microgliopathies, such as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), are neurological disorders characterized by microglial dysfunction.
- Current mouse models inadequately represent the complex neuropathologies and reduced microglial populations seen in human ALSP patients.
Purpose of the Study:
- To develop a more accurate mouse model for ALSP by targeting the Csf1r gene.
- To investigate the therapeutic potential of human induced pluripotent stem cell-derived microglial (iMG) transplantation for ALSP treatment.
Main Methods:
- Generation of a xenotolerant mouse model lacking the fms-intronic regulatory element (FIRE) enhancer in Csf1r.
- Transplantation of human iPSC-derived microglial progenitors into the developed mouse model.
- Utilizing CRISPR-corrected ALSP-patient-derived iMG for transplantation studies.
Main Results:
- The FIRE enhancer-deficient mouse model successfully recapitulated hallmark ALSP pathologies.
- Transplantation of human iMG progenitors reversed ALSP-related pathologies, including axonal spheroids, white matter abnormalities, astrocytosis, and brain calcifications.
- CRISPR-corrected iMG transplantation demonstrated reversal of pre-existing ALSP pathologies.
Conclusions:
- The FIRE mouse model serves as a valuable tool for studying ALSP.
- Human iMG transplantation presents a promising therapeutic strategy for ALSP and potentially other microglial disorders.
