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Effects of biological sex mismatch on neural progenitor cell transplantation for spinal cord injury in mice.

ABSTRACT: Despite advancement of neural progenitor cell transplantation to spinal cord injury clinical trials, there remains a lack of understanding of how biological sex of transplanted cells influences outcomes after transplantation. To address this, we transplanted GFP-expressing sex-matched, sex-mismatched, or mixed donor cells into sites of spinal cord injury in adult male and female mice. Biological sex of the donor cells does not influence graft neuron density, glial differentiation, formation of the reactive glial cell border, or graft axon outgrowth. However, male grafts in female hosts feature extensive hypervascularization accompanied by increased vascular diameter and perivascular cell density. We show greater T-cell infiltration within male-to-female grafts than other graft types. Together, these findings indicate a biological sex-specific immune response of female mice to male donor cells. Our work suggests that biological sex should be considered in the design of future clinical trials for cell transplantation in human injury.

SUBMITTER: Pitonak M

PROVIDER: S-EPMC9474813 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Effects of biological sex mismatch on neural progenitor cell transplantation for spinal cord injury in mice.

Pitonak Michael M Aceves Miriam M Kumar Prakruthi Amar PA Dampf Gabrielle G Green Peyton P Tucker Ashley A Dietz Valerie V Miranda Diego D Letchuman Sunjay S Jonika Michelle M MM Bautista David D Blackmon Heath H Dulin Jennifer N JN

Nature communications 20220914 1

Despite advancement of neural progenitor cell transplantation to spinal cord injury clinical trials, there remains a lack of understanding of how biological sex of transplanted cells influences outcomes after transplantation. To address this, we transplanted GFP-expressing sex-matched, sex-mismatched, or mixed donor cells into sites of spinal cord injury in adult male and female mice. Biological sex of the donor cells does not influence graft neuron density, glial differentiation, formation of t ...[more]

PMID: 36104357

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Project description:BackgroundTraumatic spinal cord injury (SCI) triggers a chain of events that is accompanied by an inflammatory reaction leading to necrotic cell death at the core of the injury site, which is restricted by astrogliosis and apoptotic cell death in the surrounding areas. Activation of nuclear factor-κB (NF-κB) signaling pathway has been shown to be associated with inflammatory response induced by SCI. Here, we elucidate the pattern of activation of NF-κB in the pathology of SCI in rats and investigate the effect of transplantation of spinal neural precursors (SPC-01) on its activity and related astrogliosis.MethodsUsing a rat compression model of SCI, we transplanted SPC-01 cells or injected saline into the lesion 7 days after SCI induction. Paraffin-embedded sections were used to assess p65 NF-κB nuclear translocation at days 1, 3, 7, 10, 14, and 28 and to determine levels of glial scaring, white and gray matter preservation, and cavity size at day 28 after SCI. Additionally, levels of p65 phosphorylated at Serine536 were determined 10, 14, and 28 days after SCI as well as levels of locally secreted TNF-α.ResultsWe determined a bimodal activation pattern of canonical p65 NF-κB signaling pathway in the pathology of SCI with peaks at 3 and 28 days after injury induction. Transplantation of SCI-01 cells resulted in significant downregulation of TNF-α production at 10 and 14 days after SCI and in strong inhibition of p65 NF-κB activity at 28 days after SCI, mainly in the gray matter. Moreover, reduced formation of glial scar was found in SPC-01-transplanted rats along with enhanced gray matter preservation and reduced cavity size.ConclusionsThe results of this study demonstrate strong immunomodulatory properties of SPC-01 cells based on inhibition of a major signaling pathway. Canonical NF-κB pathway activation underlines much of the immune response after SCI including cytokine, chemokine, and apoptosis-related factor production as well as immune cell activation and infiltration. Reduced inflammation may have led to observed tissue sparing. Additionally, such immune response modulation could have impacted astrocyte activation resulting in a reduced glial scar.

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Effects of biological sex mismatch on neural progenitor cell transplantation for spinal cord injury in mice.

Publications

Effects of biological sex mismatch on neural progenitor cell transplantation for spinal cord injury in mice.

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