iPSC-Derived Neural Stem Cells Act via Kinase Inhibition to Exert Neuroprotective Effects in Spinal Muscular Atrophy with Respiratory Distress Type 1

Simone, Carla; Nizzardo, Monica; Rizzo, Federica; Ruggieri, Margherita; Riboldi, Giulietta; Salani, Sabrina; Bucchia, Monica; Bresolin, Nereo; Comi, Giacomo P.; Corti, Stefania

doi:10.1016/j.stemcr.2014.06.004

Cited by 35 publications

(52 citation statements)

References 25 publications

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“…Nevertheless, these studies were able to nicely show promising properties of engrafted cells in the injured spinal cord environment, including synaptic integration into endogenous neuronal circuitry (Fujimoto et al, 2012; Nori et al, 2011). iPS cell-derived NSCs have also shown therapeutic promise in models of other spinal cord diseases such as spinal muscular atrophy (Simone et al, 2014). …”

Section: Discussionmentioning

confidence: 99%

Human iPS cell-derived astrocyte transplants preserve respiratory function after spinal cord injury

Javed

Scura

et al. 2015

Experimental Neurology

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Transplantation-based replacement of lost and/or dysfunctional astrocytes is a promising therapy for spinal cord injury (SCI) that has not been extensively explored, despite the integral roles played by astrocytes in the central nervous system (CNS). Induced pluripotent stem (iPS) cells are a clinically-relevant source of pluripotent cells that both avoid ethical issues of embryonic stem cells and allow for homogeneous derivation of mature cell types in large quantities, potentially in an autologous fashion. Despite their promise, the iPS cell field is in its infancy with respect to evaluating in vivo graft integration and therapeutic efficacy in SCI models. Astrocytes express the major glutamate transporter, GLT1, which is responsible for the vast majority of glutamate uptake in spinal cord. Following SCI, compromised GLT1 expression/function can increase susceptibility to excitotoxicity. We therefore evaluated intraspinal transplantation of human iPS cell-derived astrocytes (hIPSAs) following cervical contusion SCI as a novel strategy for reconstituting GLT1 expression and for protecting diaphragmatic respiratory neural circuitry. Transplant-derived cells showed robust long-term survival post-injection and efficiently differentiated into astrocytes in injured spinal cord of both immunesuppressed mice and rats. However, the majority of transplant-derived astrocytes did not express high levels of GLT1, particularly at early times post-injection. To enhance their ability to modulate extracellular glutamate levels, we engineered hIPSAs with lentivirus to constitutively express GLT1. Overexpression significantly increased GLT1 protein and functional GLT1-mediated glutamate uptake levels in hIPSAs both in vitro and in vivo post-transplantation. Compared to human fibroblast control and unmodified hIPSA transplantation, GLT1-overexpressing hIPSAs reduced (1) lesion size within the injured cervical spinal cord, (2) morphological denervation by respiratory phrenic motor neurons at the diaphragm neuromuscular junction, and (3) functional diaphragm denervation as measured by recording of spontaneous EMGs and evoked compound muscle action potentials. Our findings demonstrate that hiPSA transplantation is a therapeutically-powerful approach for SCI.

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Section: Discussionmentioning

confidence: 99%

Human iPS cell-derived astrocyte transplants preserve respiratory function after spinal cord injury

Javed

Scura

et al. 2015

Experimental Neurology

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“…Moreover, the injected cells demonstrated the ability to differentiate into motor neurons, migrate and send their axons into the white matter and anterior horn and provided evidence of a remarkable amelioration of the neurogenic atrophy phenotype without preventing the premature death of the nmd mice 42. The hypothesis, based on the observed data, is that this improvement may be due to the production of neurotrophins (GDNF, BDNF, NT-3 and TGF-α) and the inhibition of HGK and GSK-3 kinases 31. We observed that the treated nmd mice had higher body weights and lengths and better motility, as measured by the rotarod test.…”

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confidence: 91%

“…The factors Oct3/4, Sox2, c-Myc and Klf4 act together to overwhelm skin gene expression in fibroblasts and can activate genes encoding hESC proteins, thus inducing the reprogramming of somatic cells into iPSCs 28. Our group provided one of the first descriptions of the generation of IGHMBP2-mutated iPSCs from SMARD1 patients for in vitro studies of SMARD1 31,32. Our group provided one of the first descriptions of the generation of IGHMBP2-mutated iPSCs from SMARD1 patients for in vitro studies of SMARD1 31,32.…”

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confidence: 99%

Spinal muscular atrophy with respiratory distress type 1: Clinical phenotypes, molecular pathogenesis and therapeutic insights

Saladini

Nizzardo

Govoni

et al. 2019

J Cellular Molecular Medi

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Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder caused by mutations in the IGHMBP2 gene, which encodes immunoglobulin μ-binding protein 2, leading to progressive spinal motor neuron degeneration. We review the data available in the literature about SMARD1. The vast majority of patients show an onset of typical symptoms in the first year of life. The main clinical features are distal muscular atrophy and diaphragmatic palsy, for which permanent supportive ventilation is required. No effective treatment is available yet, but novel therapeutic approaches, such as gene therapy, have shown encouraging results in preclinical settings and thus represent possible methods for treating SMARD1. Significant advancements in the understanding of both the SMARD1 clinical spectrum and its molecular mechanisms have allowed the rapid translation of preclinical therapeutic strategies to human patients to improve the poor prognosis of this devastating disease.

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“…They also found phenotypic improvement due to motor neuron protection, suggesting trophic influences of the transplanted cells. In support of this mechanism, through in vitro co-culturing studies with motor neurons generated from human SMARD1-iPS cells, they reported that iPS cell-derived NSCs increased motor neuron axonal length via neurotrophic factor production [68]. …”

Section: Transplantation Of Ips Cells In Other Spinal Cord Disease Momentioning

confidence: 99%

iPS Cell Transplantation for Traumatic Spinal Cord Injury

Goulão¹,

Lepore²

2016

CSCR

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A large body of work has been published on transplantation of a wide range of neural stem and progenitor cell types derived from the developing and adult CNS, as well as from pluripotent embryonic stem cells, in models of traumatic spinal cord injury (SCI). However, many of these cell-based approaches present practical issues for clinical translation such as ethical cell derivation, generation of potentially large numbers of homogenously prepared cells, and immune rejection. With the advent of induced Pluripotent Stem (iPS) cell technology, many of these issues may potentially be overcome. To date, a number of studies have demonstrated integration, differentiation into mature CNS lineages, migration and long-term safety of iPS cell transplants in a variety of SCI models, as well as therapeutic benefits in some cases. Given the clinical potential of this advance in stem cell biology, we present a concise review of studies published to date involving iPS cell transplantation in animal models of SCI.

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iPSC-Derived Neural Stem Cells Act via Kinase Inhibition to Exert Neuroprotective Effects in Spinal Muscular Atrophy with Respiratory Distress Type 1

Cited by 35 publications

References 25 publications

Human iPS cell-derived astrocyte transplants preserve respiratory function after spinal cord injury

Human iPS cell-derived astrocyte transplants preserve respiratory function after spinal cord injury

Spinal muscular atrophy with respiratory distress type 1: Clinical phenotypes, molecular pathogenesis and therapeutic insights

iPS Cell Transplantation for Traumatic Spinal Cord Injury

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