Decoding the molecular crosstalk between grafted stem cells and the stroke-injured brain

Azevedo-Pereira, Ricardo Luiz; Manley, Nathan C.; Dong, Chen; Zhang, Yue; Lee, Alex G.; Zatulovskaia, Yulia A.; Gupta, Vineeta; Vu, Jennifer; Han, Summer S.; Berry, Jack; Bliss, Tonya; Steinberg, Gary K.

doi:10.1016/j.celrep.2023.112353

Cited by 3 publications

References 40 publications

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Brain repair mechanisms after cell therapy for stroke

Rust,

Nih,

Liberale

et al. 2024

Brain

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Cell-based therapies hold great promise for brain repair after stroke. While accumulating evidence confirms the preclinical and clinical benefits of cell therapies, the underlying mechanisms by which they promote brain repair remain unclear. Here, we briefly review endogenous mechanisms of brain repair after ischemic stroke and then focus on how different stem and progenitor cell sources can promote brain repair. Specifically, we examine how transplanted cell grafts contribute to improved functional recovery either through direct cell replacement or by stimulating endogenous repair pathways. Additionally, we discuss recently implemented preclinical refinement methods, such as preconditioning, microcarriers, genetic safety switches, and universal (immune evasive) cell transplants, as well as the therapeutic potential of these pharmacologic and genetic manipulations to further enhance the efficacy and safety of cell therapies. By gaining a deeper understanding of post-ischemic repair mechanisms, prospective clinical trials may be further refined to advance post-stroke cell therapy to the clinic.

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Brain repair mechanisms after cell therapy for stroke

Rust,

Nih,

Liberale

et al. 2024

Brain

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Human iPSC-derived cell grafts promote functional recovery by molecular interaction with stroke-injured brain

Weber,

Achón Buil,

Rentsch

et al. 2024

Preprint

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Stroke is a leading cause of disability and death due to the brain's limited ability to regenerate damaged neural circuits. To date, stroke patients have only few therapeutic options and are often left with considerable disabilities. Induced pluripotent stem cell (iPSC)-based therapies are emerging as a promising therapeutic approach for stroke recovery. In this study, we demonstrate that local transplantation of good manufacturing practice (GMP)-compatible iPSC-derived neural progenitor cells (NPCs) improve long-term recovery-associated brain tissue responses and reduce neurological deficits after cerebral ischemia in mice. Using in vivo bioluminescence imaging and post-mortem histology, we showed long-term graft survival over the course of five weeks and preferential graft differentiation into mature neurons without signs of pluripotent residuals. Transplantation of NPCs led to a set of recovery-associated tissue responses including increased vascular sprouting and repair, improved blood-brain barrier integrity, reduced microglial activation, and increased neurogenesis compared to littermate control animals receiving sham transplantation. Employing deep learning-assisted behavior analysis, we found that NPC-treated mice displayed improved gait performance and complete fine-motor recovery in the horizontal ladder rung walk, five weeks post-injury. To dissect the molecular graft composition and identify graft-host interactions, single nucleus profiling of the cell transplants and host stroke tissue was performed. We identified graft differentiation preferentially towards GABAergic cells with remaining cells acquiring glutamatergic neuron, astrocyte, and NPC-like phenotypes. Interaction between graft and host transcriptome indicated that GABAergic cell grafts were primarily involved in graft-host communication through the regeneration-associated NRXN, NRG, NCAM and SLIT signalling pathways. In conclusion, our study reveals that transplanted iPSC-derived NPCs primarily differentiate into GABAergic neurons contributing to long-term recovery, and further delineates the regenerative interactions between the graft and the stroke-injured host tissue.

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Human neural stem cells derived from fetal human brain communicate each other and rescue ischemic neurons through tunneling nanotubes

Pisani,

Capobianco,

De Zio

et al. 2024

Preprint

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Pre-clinical trials have demonstrated the neuroprotective effects of transplanted human neural stem cells (hNSCs) during the post-ischemic phase. However, the exact neuroprotective mechanism remains unclear. Tunneling nanotubes (TNTs) are long plasma membrane bridges that physically connect distant cells, enabling the intercellular transfer of mitochondria, contributing to post-ischemic repair processes. Whether hNSCs communicate through TNTs and their role in post-ischemic neuroprotection remain unknown. In this study, non-immortalized hNSC lines derived from fetal human brain tissues were examined to explore these possibilities and assess the post-ischemic neuroprotection potential of these hNSCs. Using Tau-STED super-resolution confocal microscopy, live cell time-lapse fluorescence microscopy, electron microscopy, and direct or non-contact homotypic co-cultures, we demonstrated that hNSCs generate nestin-positive TNTs in both 3D neurospheres and 2D cultures, though which they transfer functional mitochondria. Co-culturing hNSCs with human neurons revealed heterotypic TNTs allowing mitochondrial transfer from hNSCs to neurons. To investigate the role of heterotypic TNTs in post-ischemic neuroprotection, neurons were subjected to oxygen-glucose deprivation (OGD) followed by reoxygenation (OGD/R) with or without hNSCs in direct or non-contact co-cultures. Compared to normoxia, OGD/R neurons became apoptotic with impaired electrical activity. When OGD/R neurons were co-cultured in direct contact with hNSCs, heterotypic TNTs enabled the transfer of functional mitochondria from hNSCs to OGD/R neurons, rescuing them from apoptosis and restoring the bioelectrical profile toward normoxic neurons. This complete neuroprotection did not occur in the non-contact co-culture. In summary, our data reveal the presence of a functional TNTs network containing nestin within hNSCs, demonstrate the involvement of TNTs in post-ischemic neuroprotection mediated by hNSCs, and highlight the strong efficacy of our hNSC lines in post-ischemic neuroprotection.

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Decoding the molecular crosstalk between grafted stem cells and the stroke-injured brain

Cited by 3 publications

References 40 publications

Brain repair mechanisms after cell therapy for stroke

Brain repair mechanisms after cell therapy for stroke

Human iPSC-derived cell grafts promote functional recovery by molecular interaction with stroke-injured brain

Human neural stem cells derived from fetal human brain communicate each other and rescue ischemic neurons through tunneling nanotubes

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