Clinical translation of human neural stem cells

Tsukamoto, Ann; Uchida, Naoshige; Capela, Alexandra; Gorba, Thorsten; Huhn, Stephen L.

doi:10.1186/scrt313

Cited by 49 publications

(31 citation statements)

References 74 publications

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“…Pharmacological agents aimed at modulating Piezo1 activity may be useful in directing the fate of transplanted neural stem cells toward the desired lineage. transplantation into the central nervous system (24) and currently are in clinical trials for multiple neurological conditions (25,26).…”

Section: Resultsmentioning

confidence: 99%

Stretch-activated ion channel Piezo1 directs lineage choice in human neural stem cells

Pathak¹,

Nourse

Tran³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

505

509

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Neural stem cells are multipotent cells with the ability to differentiate into neurons, astrocytes, and oligodendrocytes. Lineage specification is strongly sensitive to the mechanical properties of the cellular environment. However, molecular pathways transducing matrix mechanical cues to intracellular signaling pathways linked to lineage specification remain unclear. We found that the mechanically gated ion channel Piezo1 is expressed by brainderived human neural stem/progenitor cells and is responsible for a mechanically induced ionic current. Piezo1 activity triggered by traction forces elicited influx of Ca 2+ , a known modulator of differentiation, in a substrate-stiffness-dependent manner. Inhibition of channel activity by the pharmacological inhibitor GsMTx-4 or by siRNA-mediated Piezo1 knockdown suppressed neurogenesis and enhanced astrogenesis. Piezo1 knockdown also reduced the nuclear localization of the mechanoreactive transcriptional coactivator Yes-associated protein. We propose that the mechanically gated ion channel Piezo1 is an important determinant of mechanosensitive lineage choice in neural stem cells and may play similar roles in other multipotent stem cells. (5) and that the mechanical properties of the culturing environment before transplantation can influence the outcome of in vivo stem cell transplants (6). Hence, a molecular and mechanistic understanding of how stem cells process mechanical cues and how this processing results in downstream signaling events and ultimately in fate decisions is needed for greater control over the fate of transplanted cells.Studies in mesenchymal and neural stem cells have revealed the involvement of focal adhesion zones and cytoskeletal proteins, such as integrins, nonmuscle myosin II (7), Rho GTPases (8-10), and vinculin (11), that participate in the generation of cellular traction forces. Recent work also has identified the nucleoskeletal protein lamin-A (12) and the transcriptional coactivators Yap (Yesassociated protein) and Taz (transcriptional coactivator with PDZbinding motif) (13) in mechanotransduction in mesenchymal stem cells. However, the mechanisms by which mechanical cues detected by cellular traction forces are transduced to downstream intracellular pathways of differentiation remain unclear.Ion channels are involved, directly or indirectly, in the transduction of all forms of physical stimuli-including sound, light, temperature, mechanical force, and even gravity-into intracellular signaling pathways. Hence, we wondered whether ion channels could be involved in transducing matrix mechanical cues to intracellular signaling pathways linked to lineage specification. In particular, we focused here on cationic stretch-activated channels (SACs) because they are known to detect mechanical forces with high sensitivity and broad dynamic range and because they are permeable to Ca 2+ , an important second messenger implicated in cell fate (14,15). We examined the role of SACs in neural stem cells, for which mechanical cues influence specification alo...

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Section: Resultsmentioning

confidence: 99%

Stretch-activated ion channel Piezo1 directs lineage choice in human neural stem cells

Pathak¹,

Nourse

Tran³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

505

509

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“…iPSC-derived NSCs could migrate toward brain tumors and thus are being studied as gene or drug delivery vehicles for treating brain cancers61. NSCs isolated from fetal brains have been in clinical trials for treating a few rare neuronal degenerative diseases62. iPSC-derived NSCs have potential to replace these fetal NSCs to avoid the ethical issues and host immune response.…”

Section: Discussionmentioning

confidence: 99%

An Integrated Miniature Bioprocessing for Personalized Human Induced Pluripotent Stem Cell Expansion and Differentiation into Neural Stem Cells

Lin

Lei

2017

Sci Rep

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Human induced pluripotent stem cells (iPSCs) are ideal cell sources for personalized cell therapies since they can be expanded to generate large numbers of cells and differentiated into presumably all the cell types of the human body in vitro. In addition, patient specific iPSC-derived cells induce minimal or no immune response in vivo. However, with current cell culture technologies and bioprocessing, the cost for biomanufacturing clinical-grade patient specific iPSCs and their derivatives are very high and not affordable for majority of patients. In this paper, we explored the use of closed and miniature cell culture device for biomanufacturing patient specific neural stem cells (NSCs) from iPSCs. We demonstrated that, with the assist of a thermoreversible hydrogel scaffold, the bioprocessing including iPSC expansion, iPSC differentiation into NSCs, the subsequent depletion of undifferentiated iPSCs from the NSCs, and concentrating and transporting the purified NSCs to the surgery room, could be integrated and completed within two closed 15 ml conical tubes.

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“…1 Neural stem cell (NSC) transplant populations offer important therapeutic potential for such patients, mediating repair in multiple pre-clinical disease models including Parkinson's disease, multiple sclerosis and stroke 2,1 with multiple clinical trials underway. NeuralStem (USA) is currently undertaking a phase I clinical trial (NCT01348451) for amyotrophic lateral sclerosis.…”

Section: Introductionmentioning

confidence: 99%

Deploying clinical grade magnetic nanoparticles with magnetic fields to magnetolabel neural stem cells in adherent versus suspension cultures

2015

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Clinical translation of human neural stem cells

Cited by 49 publications

References 74 publications

Stretch-activated ion channel Piezo1 directs lineage choice in human neural stem cells

Stretch-activated ion channel Piezo1 directs lineage choice in human neural stem cells

An Integrated Miniature Bioprocessing for Personalized Human Induced Pluripotent Stem Cell Expansion and Differentiation into Neural Stem Cells

Deploying clinical grade magnetic nanoparticles with magnetic fields to magnetolabel neural stem cells in adherent versus suspension cultures

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