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Updated: Dec 27, 2025
Transplantation of Human Induced Pluripotent Stem Cell-Derived Microglia in Immunocompetent Mice Brain via Non-Invasive Transnasal Route
Published on: May 31, 2022
Tolerance induction and microglial engraftment after fetal therapy without conditioning in mice with
Quoc-Hung Nguyen1,2, Russell G Witt1,2, Bowen Wang1,2
1Eli and Edythe Broad Center of Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Abstract:
Mucopolysaccharidosis type VII (MPS7) is a lysosomal storage disorder (LSD) resulting from mutations in the β-glucuronidase gene, leading to multiorgan dysfunction and fetal demise. While postnatal enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation have resulted in some phenotypic improvements, prenatal treatment might take advantage of a unique developmental window to penetrate the blood-brain barrier or induce tolerance to the missing protein, addressing two important shortcomings of postnatal therapy for multiple LSDs. We performed in utero ERT (IUERT) at E14.5 in MPS7 mice and improved survival of affected mice to birth. IUERT penetrated brain microglia, whereas postnatal administration did not, and neurological testing (after IUERT plus postnatal administration) showed decreased microglial inflammation and improved grip strength in treated mice. IUERT prevented antienzyme antibody development even after multiple repeated postnatal challenges. To test a more durable treatment strategy, we performed in utero hematopoietic stem cell transplantation (IUHCT) using congenic CX3C chemokine receptor 1-green fluorescent protein (CX3CR1-GFP) mice as donors, such that donor-derived microglia are identified by GFP expression. In wild-type recipients, hematopoietic chimerism resulted in microglial engraftment throughout the brain without irradiation or conditioning; the transcriptomes of donor and host microglia were similar. IUHCT in MPS7 mice enabled cross-correction of liver Kupffer cells and improved phenotype in multiple tissues. Engrafted microglia were seen in chimeric mice, with decreased inflammation near donor microglia. These results suggest that fetal therapy with IUERT and/or IUHCT could overcome the shortcomings of current treatment strategies to improve phenotype in MPS7 and other LSDs.
Insights
Prenatal enzyme replacement therapy and stem cell transplantation in MPS7 mice improved survival and reduced inflammation. Fetal therapies show promise for treating lysosomal storage disorders before birth.
Area of Science:
- Genetics and Molecular Biology
- Developmental Biology
- Immunology
Background:
- Mucopolysaccharidosis type VII (MPS7) is a genetic lysosomal storage disorder causing severe multi-organ dysfunction and often fetal demise.
- Current postnatal treatments like enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) have limitations, including poor blood-brain barrier penetration and potential immune rejection.
- Prenatal interventions could offer advantages by utilizing a developmental window for improved therapeutic efficacy and immune tolerance.
Purpose of the Study:
- To evaluate the efficacy of in utero enzyme replacement therapy (IUERT) and in utero hematopoietic stem cell transplantation (IUHCT) for MPS7.
- To assess the potential of fetal therapies to overcome limitations of postnatal treatments for lysosomal storage disorders.
- To investigate the impact of prenatal treatment on microglial engraftment, inflammation, and overall phenotype in MPS7 mice.
Main Methods:
- In utero ERT (IUERT) was administered to MPS7 mice at embryonic day 14.5.
- In utero HSCT (IUHCT) was performed using congenic CX3CR1-GFP mice as donors.
- Neurological testing, microglial analysis, and assessment of immune responses (antibody development) were conducted.
- Hematopoietic chimerism and microglial engraftment were analyzed in wild-type and MPS7 recipients.
Main Results:
- IUERT improved survival of MPS7 mice to birth and enabled enzyme delivery to brain microglia, unlike postnatal ERT.
- IUERT and subsequent postnatal administration reduced microglial inflammation and improved grip strength in treated mice.
- IUERT prevented the development of anti-enzyme antibodies, even after repeated postnatal challenges.
- IUHCT in MPS7 mice led to microglial engraftment, cross-correction of liver Kupffer cells, and improved multi-tissue phenotype with reduced inflammation.
- Donor microglia engrafted in the brain of wild-type recipients without conditioning, showing similar transcriptomes to host microglia.
Conclusions:
- Fetal therapies, including IUERT and IUHCT, demonstrate significant potential to overcome critical shortcomings of current postnatal treatments for MPS7.
- Prenatal interventions may enhance enzyme delivery to the central nervous system and establish immune tolerance, crucial for treating lysosomal storage disorders.
- These findings support the development of in utero strategies as a more durable and effective treatment for MPS7 and potentially other LSDs.
