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Targeted transplantation of engineered mitochondrial compound promotes functional recovery after spinal cord injury by enhancing macrophage phagocytosis.

ABSTRACT: Mitochondria are crucial in sustaining and orchestrating cellular functions. Capitalizing on this, we explored mitochondrial transplantation as an innovative therapeutic strategy for acute spinal cord injury (SCI). In our study, we developed an engineered mitochondrial compound tailored to target macrophages within the SCI region. Sourced from IL-10-induced Mertk^hi bone marrow-derived macrophages, we conjugated a peptide sequence, cations-cysteine-alanine-glutamine-lysine (CAQK), with the mitochondria, optimizing its targeting affinity for the injury site. Our data demonstrated that these compounds significantly enhanced macrophage phagocytosis of myelin debris, curtailed lipid buildup, ameliorated mitochondrial dysfunction, and attenuated pro-inflammatory profiles in macrophages, both in vitro and in vivo. The intravenously delivered mitochondrial compounds targeted the SCI epicenter, with macrophages being the primary recipients. Critically, they promoted tissue regeneration and bolstered functional recovery in SCI mice. This study heralds a transformative approach to mitochondrial transplantation in SCI, spotlighting the modulation of macrophage activity, phagocytosis, and phenotype.

SUBMITTER: Xu J

PROVIDER: S-EPMC10632560 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Targeted transplantation of engineered mitochondrial compound promotes functional recovery after spinal cord injury by enhancing macrophage phagocytosis.

Xu Jiaqi J Shi Chaoran C Yuan Feifei F Ding Yinghe Y Xie Yong Y Liu Yudong Y Zhu Fengzhang F Lu Hongbin H Duan Chunyue C Hu Jianzhong J Jiang Liyuan L

Bioactive materials 20231027

Mitochondria are crucial in sustaining and orchestrating cellular functions. Capitalizing on this, we explored mitochondrial transplantation as an innovative therapeutic strategy for acute spinal cord injury (SCI). In our study, we developed an engineered mitochondrial compound tailored to target macrophages within the SCI region. Sourced from IL-10-induced Mertk<sup>hi</sup> bone marrow-derived macrophages, we conjugated a peptide sequence, cations-cysteine-alanine-glutamine-lysine (CAQK), with ...[more]

PMID: 37954465

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Project description:Repairing trauma to the central nervous system by replacement of glial support cells is an increasingly attractive therapeutic strategy. We have focused on the less-studied replacement of astrocytes, the major support cell in the central nervous system, by generating astrocytes from embryonic human glial precursor cells using two different astrocyte differentiation inducing factors. The resulting astrocytes differed in expression of multiple proteins thought to either promote or inhibit central nervous system homeostasis and regeneration. When transplanted into acute transection injuries of the adult rat spinal cord, astrocytes generated by exposing human glial precursor cells to bone morphogenetic protein promoted significant recovery of volitional foot placement, axonal growth and notably robust increases in neuronal survival in multiple spinal cord laminae. In marked contrast, human glial precursor cells and astrocytes generated from these cells by exposure to ciliary neurotrophic factor both failed to promote significant behavioral recovery or similarly robust neuronal survival and support of axon growth at sites of injury. Our studies thus demonstrate functional differences between human astrocyte populations and suggest that pre-differentiation of precursor cells into a specific astrocyte subtype is required to optimize astrocyte replacement therapies. To our knowledge, this study is the first to show functional differences in ability to promote repair of the injured adult central nervous system between two distinct subtypes of human astrocytes derived from a common fetal glial precursor population. These findings are consistent with our previous studies of transplanting specific subtypes of rodent glial precursor derived astrocytes into sites of spinal cord injury, and indicate a remarkable conservation from rat to human of functional differences between astrocyte subtypes. In addition, our studies provide a specific population of human astrocytes that appears to be particularly suitable for further development towards clinical application in treating the traumatically injured or diseased human central nervous system.

Dataset Information

Targeted transplantation of engineered mitochondrial compound promotes functional recovery after spinal cord injury by enhancing macrophage phagocytosis.

Publications

Targeted transplantation of engineered mitochondrial compound promotes functional recovery after spinal cord injury by enhancing macrophage phagocytosis.

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