Activation of Innate and Adaptive Immunity in the Central Nervous System Following Xenogeneic Mesenchymal Stromal Cell Transplantation
5 affiliations
- 1Experimental Ophthalmology Research Group, Department of Ophthalmology, Optometry, Otorhinolaryngology, and Pathological Anatomy, Faculty of Optics and Optometry, University of Murcia, 30100 Murcia, Spain
- 2Instituto Murciano de Investigación Biosanitaria Pascual Parrilla (IMIB), 30120 Murcia, Spain
- 3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, NY 10461, USA
- 4Immunity, Inflammation, and Cancer Research Group, Department of Cell Biology and Histology, Faculty of Biology, University of Murcia, 30100 Murcia, Spain
- 5Hematopoietic Transplantation and Cellular Therapy Research Group, Department of Biochemistry, Molecular Biology and Immunology, Faculty of Medicine, University of Murcia, 30120 Murcia, Spain
Abstract
Stem cell-based therapies have emerged as promising strategies for neurodegenerative disorders, partly supported by the concept of central nervous system immune privilege, which has encouraged xenogeneic transplantation approaches under the assumption of limited host immune responses. However, the immunological consequences of xenogeneic cell delivery into the central nervous system remain poorly characterized. In this study, we investigated the immune response elicited by intravitreal transplantation of human bone marrow-derived mesenchymal stromal cells (BM-MSCs) into healthy mouse retinas. Twenty-one days after transplantation, retinal CD45+ and/or CD11b+ cells, including microglia, macrophages, and infiltrating leukocytes, were isolated and subjected to exploratory single-cell RNA sequencing. Candidate immune cell populations and pathways identified transcriptomically were subsequently evaluated by immunostaining, flow cytometry, and plasma antibody analyses. Xenogeneic BM-MSC transplantation induced marked transcriptional changes consistent with immune activation, enhanced antigen presentation, and leukocyte recruitment, features that are not typically associated with central nervous system homeostasis. These findings were supported by complementary cellular and systemic analyses, collectively revealing innate and adaptive immune responses directed against the transplanted human cells. The results demonstrate that xenogeneic BM-MSC transplantation can overcome local immune regulatory mechanisms and trigger robust immune activation within the healthy retina. These findings identify previously underappreciated immunological barriers to xenogeneic stem cell-based therapies and reveal coordinated innate and adaptive immune responses despite the presumed immune privilege of the CNS. Consideration of these immune responses will be essential for the safe and effective translation of regenerative therapies.
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BibTeX
@article{nortemunoz2026activation,
title = {{Activation of Innate and Adaptive Immunity in the Central Nervous System Following Xenogeneic Mesenchymal Stromal Cell Transplantation}},
author = {María Norte-Muñoz and Joaquín Cantón-Sandoval and Fernando Lucas-Ruiz and Victoriano Mulero and Marta Agudo-Barriuso and David García-Bernal},
journal = {Cells},
year = {2026},
month = oct,
doi = {10.3390/cells15211966},
url = {https://www.mdpi.com/2073-4409/15/21/1966},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Activation of Innate and Adaptive Immunity in the Central Nervous System Following Xenogeneic Mesenchymal Stromal Cell Transplantation
AU - María Norte-Muñoz
AU - Joaquín Cantón-Sandoval
AU - Fernando Lucas-Ruiz
AU - Victoriano Mulero
AU - Marta Agudo-Barriuso
AU - David García-Bernal
PY - 2026
DA - 2026/10/28
JO - Cells
DO - 10.3390/cells15211966
UR - https://www.mdpi.com/2073-4409/15/21/1966
AB - Stem cell-based therapies have emerged as promising strategies for neurodegenerative disorders, partly supported by the concept of central nervous system immune privilege, which has encouraged xenogeneic transplantation approaches under the assumption of limited host immune responses. However, the immunological consequences of xenogeneic cell delivery into the central nervous system remain poorly characterized. In this study, we investigated the immune response elicited by intravitreal transplantation of human bone marrow-derived mesenchymal stromal cells (BM-MSCs) into healthy mouse retinas. Twenty-one days after transplantation, retinal CD45+ and/or CD11b+ cells, including microglia, macrophages, and infiltrating leukocytes, were isolated and subjected to exploratory single-cell RNA sequencing. Candidate immune cell populations and pathways identified transcriptomically were subsequently evaluated by immunostaining, flow cytometry, and plasma antibody analyses. Xenogeneic BM-MSC transplantation induced marked transcriptional changes consistent with immune activation, enhanced antigen presentation, and leukocyte recruitment, features that are not typically associated with central nervous system homeostasis. These findings were supported by complementary cellular and systemic analyses, collectively revealing innate and adaptive immune responses directed against the transplanted human cells. The results demonstrate that xenogeneic BM-MSC transplantation can overcome local immune regulatory mechanisms and trigger robust immune activation within the healthy retina. These findings identify previously underappreciated immunological barriers to xenogeneic stem cell-based therapies and reveal coordinated innate and adaptive immune responses despite the presumed immune privilege of the CNS. Consideration of these immune responses will be essential for the safe and effective translation of regenerative therapies.
SN - 2073-4409
ER -