Stem Cell Therapy for the Central Nervous System in Lysosomal Storage Diseases

Siddiqi, F.; Wolfe, John H.

doi:10.1089/hum.2016.088

Cited by 14 publications

(18 citation statements)

References 122 publications

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“…Recent scientific advances in stem cell research have opened new avenues for studying various human diseases and promote drug development in a dish [100, 101, 102, 103, 104]. Both, pluripotent and adult stem cells exhibit significant self-renewal capacity and can acquire any specialized cell genotype/phenotype under cue-directed differentiation for high throughput in vitro disease modeling and toxicity testing [105, 106, 107, 108, 109].…”

Section: The Near Future: Stem Cell Based Bbb Modelsmentioning

confidence: 99%

New experimental models of the blood-brain barrier for CNS drug discovery

Kaisar

Sajja

Prasad

et al. 2016

Expert Opinion on Drug Discovery

104

108

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Introduction The blood-brain barrier (BBB) is a dynamic biological interface which actively controls the passage of substances between the blood and the central nervous system (CNS). From a biological and functional standpoint, the BBB plays a crucial role in maintaining brain homeostasis inasmuch that deterioration of BBB functions are prodromal to many CNS disorders. Conversely, the BBB hinders the delivery of drugs targeting the brain to treat a variety of neurological diseases. Area covered This article reviews recent technological improvements and innovation in the field of BBB modeling including static and dynamic cell-based platforms, microfluidic systems and the use of stem cells and 3D printing technologies. Additionally, the authors laid out a roadmap for the integration of microfluidics and stem cell biology as a holistic approach for the development of novel in vitro BBB platforms. Expert opinion Development of effective CNS drugs has been hindered by the lack of reliable strategies to mimic the BBB and cerebrovascular impairments in vitro. Technological advancements in BBB modeling have fostered the development of highly integrative and quasi- physiological in vitro platforms to support the process of drug discovery. These advanced in vitro tools are likely to further current understanding of the cerebrovascular modulatory mechanisms.

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Section: The Near Future: Stem Cell Based Bbb Modelsmentioning

confidence: 99%

New experimental models of the blood-brain barrier for CNS drug discovery

Kaisar

Sajja

Prasad

et al. 2016

Expert Opinion on Drug Discovery

104

108

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“…Tissue stem cells offer a promising therapeutic option for the prevention and treatment of a number of diseases, such as neurological, autoimmune and cardiovascular disorders, and various cancers, e.g., leukemia [1][2][3][4][5][6]. Herein,…”

Section: Introductionmentioning

confidence: 99%

Direct conversion of human fibroblasts into therapeutically active vascular wall-typical mesenchymal stem cells

Steens

Unger

Klar

et al. 2019

Cell. Mol. Life Sci.

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Cell-based therapies using adult stem cells are promising options for the treatment of a number of diseases including autoimmune and cardiovascular disorders. Among these, vascular wall-derived mesenchymal stem cells (VW-MSCs) might be particularly well suited for the protection and curative treatment of vascular damage because of their tissue-specific action. Here we report a novel method for the direct conversion of human skin fibroblasts towards MSCs using a VW-MSC-specific gene code (HOXB7, HOXC6 and HOXC8) that directs cell fate conversion bypassing pluripotency. This direct programming approach using either a self-inactivating (SIN) lentiviral vector expressing the VW-MSC-specific HOX-code or a tetracyclinecontrolled Tet-On system for doxycycline-inducible gene expressions of HOXB7, HOXC6 and HOXC8 successfully mediated the generation of VW-typical MSCs with classical MSC characteristics in vitro and in vivo. The induced VW-MSCs (iVW-MSCs) fulfilled all criteria of MSCs as defined by the International Society for Cellular Therapy (ISCT). In terms of multipotency and clonogenicity, which are important specific properties to discriminate MSCs from fibroblasts, iVW-MSCs behaved like primary ex vivo isolated VW-MSCs and shared similar molecular and DNA methylation signatures. With respect to their therapeutic potential, these cells suppressed lymphocyte proliferation in vitro, and protected mice against vascular damage in a mouse model of radiation-induced pneumopathy in vivo, as well as ex vivo cultured human lung tissue. The feasibility to obtain patient-specific VW-MSCs from fibroblasts in large amounts by a direct conversion into induced VW-MSCs could potentially open avenues towards novel, MSC-based therapies.

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“…Thus, similarly as for spinal trauma, subpial delivery of OPS or hNSCs can be used to restore segmental myelination and function. Fourth, the use of cell‐replacement‐based therapies for the treatment of lysosomal storage disease by delivering genetically modified cells into the CNS can potentially benefit from the widespread cell repopulation achieved after subpial cell delivery . Finally, there is long lasting interest to employ autologous or allogeneic cells genetically modified to produce antinociceptive inhibitory neurotransmitters such as GABA for the treatment of chronic neuropathic pain .…”

Section: Discussionmentioning

confidence: 99%

“…Fourth, the use of cell-replacement-based therapies for the treatment of lysosomal storage disease by delivering genetically modified cells into the CNS can potentially benefit from the widespread cell repopulation achieved after subpial cell delivery. 29,30 Finally, there is long lasting interest to employ autologous or allogeneic cells genetically modified to produce antinociceptive inhibitory neurotransmitters such as GABA for the treatment of chronic neuropathic pain. [31][32][33] By using a regional subpial injection of such cells, a regionally targeted release of GABA could be achieved and potentially lead to a long lasting, anti-nociceptive effect.…”

Section: Mechanisms Of Cell Migration Into the Spinal Parenchyma Afmentioning

confidence: 99%

Spinal parenchymal occupation by neural stem cells after subpial delivery in adult immunodeficient rats

Maršala

Kamizato

Tadokoro

et al. 2019

Stem Cells Translational Medicine

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Neural precursor cells (NSCs) hold great potential to treat a variety of neurodegenerative diseases and injuries to the spinal cord. However, current delivery techniques require an invasive approach in which an injection needle is advanced into the spinal parenchyma to deliver cells of interest. As such, this approach is associated with an inherent risk of spinal injury, as well as a limited delivery of cells into multiple spinal segments.Here, we characterize the use of a novel cell delivery technique that employs single bolus cell injections into the spinal subpial space. In immunodeficient rats, two subpial injections of human NSCs were performed in the cervical and lumbar spinal cord, respectively. The survival, distribution, and phenotype of transplanted cells were assessed 6-8 months after injection. Immunofluorescence staining and mRNA sequencing analysis demonstrated a near-complete occupation of the spinal cord by injected cells, in which transplanted human NSCs (hNSCs) preferentially acquired glial phenotypes, expressing oligodendrocyte (Olig2, APC) or astrocyte (GFAP) markers. In the outermost layer of the spinal cord, injected hNSCs differentiated into glia limitans-forming astrocytes and expressed human-specific superoxide dismutase and laminin. All animals showed normal neurological function for the duration of the analysis. These data show that the subpial cell delivery technique is highly effective in populating the entire spinal cord with injected NSCs, and has a potential for clinical use in cell replacement therapies for the treatment of ALS, multiple sclerosis, or spinal cord injury. K E Y W O R D S glia limitans formation from grafted neural precursors, human-specific mRNA sequencing, immunodeficient rat, neuraxial neural precursor migration, subpial stem cell injection 1 | BACKGROUND The use of spinally targeted cell-replacement therapies for the treatment of a variety of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and spinal cord injury (SCI), has recently reached the clinical trial stage with several phase I or phase II trials underway.Extensive preclinical studies in rodent and large animal models of ALS and SCI have tested several spinal cell delivery techniques to define the most effective and safe cell delivery approach to be used in human clinical trials.

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Stem Cell Therapy for the Central Nervous System in Lysosomal Storage Diseases

Cited by 14 publications

References 122 publications

New experimental models of the blood-brain barrier for CNS drug discovery

New experimental models of the blood-brain barrier for CNS drug discovery

Direct conversion of human fibroblasts into therapeutically active vascular wall-typical mesenchymal stem cells

Spinal parenchymal occupation by neural stem cells after subpial delivery in adult immunodeficient rats

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