Host sex and transplanted human induced pluripotent stem cell phenotype interact to influence sensorimotor recovery in a mouse model of cortical contusion injury

Nieves, Michael D.; Furmanski, Orion; Doughty, Martin L.

doi:10.1016/j.brainres.2020.147120

Cited by 6 publications

(3 citation statements)

References 52 publications

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“…One recent study on acute (1-day post-injury) transplantation of human iPSC-derived NPCs in a mouse contusion model found no positive functional effects. 68 …”

Section: Cell Transplantation In Cns Traumamentioning

confidence: 99%

Stem Cell Therapies for Central Nervous System Trauma: The 4 Ws—What, When, Where, and Why

Sundström

2022

Stem Cells Translational Medicine

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Traumatic injury of the central nervous system (CNS) is a worldwide health problem affecting millions of people. Trauma of the CNS, that is, traumatic brain injury (TBI) and spinal cord injury (SCI), lead to massive and progressive cell loss and axonal degeneration, usually with very limited regeneration. At present, there are no treatments to protect injured CNS tissue or to replace the lost tissue. Stem cells are a cell type that by definition can self-renew and give rise to multiple cell lineages. In recent years, therapies using stem and progenitor cells have shown promising effects in experimental CNS trauma, particularly in the acute-subacute stage, but also in chronic injuries. However, the therapeutic mechanisms by which transplanted cells achieve the structural and/or functional improvements are often not clear. Stem cell therapies for CNS trauma can be categorized into 2 main concepts, transplantation of exogenous neural stem cells and neural progenitor cells and recruitment of endogenous stem and progenitor cells. In this review, focusing on the advances during the last decade, we will discuss the major cell therapies, the pros and cons of these 2 concepts for TBI and SCI, and the treatment strategies we believe will be successful.

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“…One recent study on acute (1-day post-injury) transplantation of human iPSC-derived NPCs in a mouse contusion model found no positive functional effects. 68 …”

Section: Cell Transplantation In Cns Traumamentioning

confidence: 99%

Stem Cell Therapies for Central Nervous System Trauma: The 4 Ws—What, When, Where, and Why

Sundström

2022

Stem Cells Translational Medicine

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“…Repair and regeneration of damaged neurons has been a longstanding goal for regenerative medicine (see Farzaneh et al, 2020 for a recent review). In addition to transplanted mesenchymal stromal cells (MSCs), neural progenitors have also been the subject of testing for clinical trials (eight on-going or completed www.clinicaltrials.gov ) for brain repair (Nieves et al, 2020 ) or spinal cord injury (Kamata et al, 2021 ). Recognizing the key role they play in CNS function, glia are being considered for replacement as well (Balakrishnan et al, 2020 ).…”

Section: Complementing and Building On Animal Models With Human Stem Cell Modelsmentioning

confidence: 99%

Building on a Solid Foundation: Adding Relevance and Reproducibility to Neurological Modeling Using Human Pluripotent Stem Cells

Knock

Julian

2021

Front. Cell. Neurosci.

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The brain is our most complex and least understood organ. Animal models have long been the most versatile tools available to dissect brain form and function; however, the human brain is highly distinct from that of standard model organisms. In addition to existing models, access to human brain cells and tissues is essential to reach new frontiers in our understanding of the human brain and how to intervene therapeutically in the face of disease or injury. In this review, we discuss current and developing culture models of human neural tissue, outlining advantages over animal models and key challenges that remain to be overcome. Our principal focus is on advances in engineering neural cells and tissue constructs from human pluripotent stem cells (PSCs), though primary human cell and slice culture are also discussed. By highlighting studies that combine animal models and human neural cell culture techniques, we endeavor to demonstrate that clever use of these orthogonal model systems produces more reproducible, physiological, and clinically relevant data than either approach alone. We provide examples across a range of topics in neuroscience research including brain development, injury, and cancer, neurodegenerative diseases, and psychiatric conditions. Finally, as testing of PSC-derived neurons for cell replacement therapy progresses, we touch on the advancements that are needed to make this a clinical mainstay.

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“…By using mild injury parameters within an open‐skull model, the injury results in categorically mild tissue pathology including reduced blood–brain barrier (BBB) integrity but without the possibility of uncontrolled skull fracture seen in closed‐head injury models (Siebold et al., 2018). The low‐velocity contusion (1.5 m/s) and shallow depth (1 mm) of the CCI avoids tissue loss in the cortex and underlying structures yet instigates a period of cortical inflammation including astrocyte and microglial activation (gliosis) and BBB compromise (Nieves et al., 2020; Radomski et al., 2013). Additionally, by targeting the primary somatosensory and motor cortices, we are able to track cognate sensorimotor deficits up to 8 weeks post‐injury (PI).…”

Section: Introductionmentioning

confidence: 99%

Sensorimotor dysfunction in a mild mouse model of cortical contusion injury without significant neuronal loss is associated with increases in inflammatory proteins with innate but not adaptive immune functions

Nieves

Furmanski

Doughty

2020

J of Neuroscience Research

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Traumatic brain injury is a leading cause of mortality and morbidity in the United States. Acute trauma to the brain triggers chronic secondary injury mechanisms that contribute to long-term neurological impairment. We have developed a single, unilateral contusion injury model of sensorimotor dysfunction in adult mice. By targeting a topographically defined neurological circuit with a mild impact, we are able to track sustained behavioral deficits in sensorimotor function in the absence of tissue cavitation or neuronal loss in the contused cortex of these mice. Stereological histopathology and multiplex enzyme-linked immunosorbent assay proteomic screening confirm contusion resulted in chronic gliosis and the robust expression of innate immune cytokines and monocyte attractant chemokines IL-1β, IL-5, IL-6, TNFα, CXCL1, CXCL2, CXCL10, CCL2, and CCL3 in the contused cortex. In contrast, the expression of neuroinflammatory proteins with adaptive immune functions was not significantly modulated by injury. Our data support widespread activation of innate but not adaptive immune responses, confirming an association between sensorimotor dysfunction with innate immune activation in the absence of tissue or neuronal loss in our mice.

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Host sex and transplanted human induced pluripotent stem cell phenotype interact to influence sensorimotor recovery in a mouse model of cortical contusion injury

Cited by 6 publications

References 52 publications

Stem Cell Therapies for Central Nervous System Trauma: The 4 Ws—What, When, Where, and Why

Stem Cell Therapies for Central Nervous System Trauma: The 4 Ws—What, When, Where, and Why

Building on a Solid Foundation: Adding Relevance and Reproducibility to Neurological Modeling Using Human Pluripotent Stem Cells

Sensorimotor dysfunction in a mild mouse model of cortical contusion injury without significant neuronal loss is associated with increases in inflammatory proteins with innate but not adaptive immune functions

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