Clinical Trials in a Dish: The Potential of Pluripotent Stem Cells to Develop Therapies for Neurodegenerative Diseases

Haston, Kelly; Finkbeiner, Steven

doi:10.1146/annurev-pharmtox-010715-103548

Cited by 74 publications

(68 citation statements)

References 147 publications

(179 reference statements)

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“…1-3 Cell replacement therapies hold great promise for neuronal regeneration and CNS functional recovery. 4,5 Specifically, human induced pluripotent stem cells (hiPSCs) reprogrammed from somatic cells have been recently recognized as a promising cell source for personalized therapies by using the patient's autologous cells. 6,7 Moreover, hiPSCs have been successfully differentiated into neural progenitor cells (NPCs) and then various CNS related cell phenotypes including neurons and glial cells, which are significantly invaluable for in vitro disease modeling, drug discovery, and developing regenerative therapies.…”

Section: Introductionmentioning

confidence: 99%

Three-dimensional hyaluronic acid hydrogel-based models for in vitro human iPSC-derived NPC culture and differentiation

Duan

et al. 2017

J. Mater. Chem. B

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Human induced pluripotent stem cell-derived neural progenitor cells (hiPSC-NPCs) are considered as a promising cell source for transplantation and have been used for organoid fabrication to recapitulate central nervous system (CNS) diseases in vitro. The establishment of three-dimensional (3D) in vitro model with hiPSC-NPCs and control of their differentiation is significantly critical for understanding biological processes and CNS disease and regeneration. Here we implemented 3D methacrylated hyaluronic acid (Me-HA) hydrogels with encapsulation of hiPSC-NPCs as in vitro culture models and further investigated the role of the hydrogel rigidity on the cell behavior of hiPSC-NPCs. We first encapsulated single dispersive hiPSC-NPCs within both soft and stiff Me-HA hydrogel and found that hiPSC-NPCs gradually self-assembled and aggregated to form 3D spheroids. Then, the hiPSC-NPCs were laden into Me-HA hydrogels in the form of spheroids to evaluate their spontaneous differentiation in response to hydrogel rigidity. The soft Me-HA hydrogel-encapsulated hiPSC-NPCs displayed robust neurite outgrowth and showed high levels of spontaneous neural differentiation. We further encapsulated Down Syndrome (DS) patient-specific hiPSC-derived NPCs (DS-NPCs) spheroids within our hydrogels. DS-NPCs remained excellent cell viability in both soft and stiff Me-HA hydrogels. Similarly, soft hydrogels promoted neural differentiation of DS-NPCs by significantly upregulating neural maturation markers. This study demonstrates that soft matrix promotes neural differentiation of hiPSC-NPCs and HA-based hydrogels with hiPSC-NPCs or DS-NPCs are effective 3D models for CNS disease study.

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Section: Introductionmentioning

confidence: 99%

Three-dimensional hyaluronic acid hydrogel-based models for in vitro human iPSC-derived NPC culture and differentiation

Duan

et al. 2017

J. Mater. Chem. B

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“…Therefore, it is not surprising that modeling autism through generation of iPSCs is currently an emerging topic. Potential advantages and disadvantages of using iPSCs in other neurodevelopmental research and in ASD are widely discussed and reviewed in (Okano & Yamanaka 2014;Srikanth & Young-Pearse 2014;Haston & Finkbeiner 2015;Payne et al 2015;Sullivan & Young-Pearse 2015;Wan et al 2015;Zhang et al 2015).…”

Section: Autistic Networkmentioning

confidence: 99%

Modeling the autistic cell: iPSCs recapitulate developmental principles of syndromic and nonsyndromic ASD

Ben-Reuven

Reiner

2016

Dev Growth Differ

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The opportunity to model autism spectrum disorders (ASD) through generation of patient-derived induced pluripotent stem cells (iPSCs) is currently an emerging topic. Wide-scale research of altered brain circuits in syndromic ASD, including Rett Syndrome, Fragile X Syndrome, Angelman's Syndrome and sporadic Schizophrenia, was made possible through animal models. However, possibly due to species differences, and to the possible contribution of epigenetics in the pathophysiology of these diseases, animal models fail to recapitulate many aspects of ASD. With the advent of iPSCs technology, 3D cultures of patient-derived cells are being used to study complex neuronal phenotypes, including both syndromic and nonsyndromic ASD. Here, we review recent advances in using iPSCs to study various aspects of the ASD neuropathology, with emphasis on the efforts to create in vitro model systems for syndromic and nonsyndromic ASD. We summarize the main cellular activity phenotypes and aberrant genetic interaction networks that were found in iPSC-derived neurons of syndromic and nonsyndromic autistic patients.

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“…One reason is that the current preclinical models solely rely on humanized transgenic animal models with poor translational capacity. This leads to the necessity for disease models that better reflect the in vivo phenotype and relate to human physiology (Haston and Finkbeiner 2016). Furthermore, animal models are not a valid system for predictive toxicology, since a chemical can be harmless in the animal model, but toxic in humans (Singh et al 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Since these factors are not routinely tested in human tissue before a drug compound enters clinical trials, development becomes more time consuming and costly. hESC-and hiPSC-derived toxicity screening models provide a possibility to overcome these issues by identifying problematic drugs before they enter clinical phase trials, where they would fail due to cytotoxicity at later stages (Ebert et al 2012;Haston and Finkbeiner 2016;Laustriat et al 2010;Sartipy and Bjorquist 2011;Singh et al 2015). Furthermore, disease-specific hESC or hiPSC can be used for drug screening assays (Singh et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Full biological characterization of human pluripotent stem cells will open the door to translational research

et al. 2016

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Since the discovery of human embryonic stem cells (hESC) and human-induced pluripotent stem cells (hiPSC), great hopes were held for their therapeutic application including disease modeling, drug discovery screenings, toxicological screenings and regenerative therapy. hESC and hiPSC have the advantage of indefinite self-renewal, thereby generating an inexhaustible pool of cells with, e.g., specific genotype for developing putative treatments; they can differentiate into derivatives of all three germ layers enabling autologous transplantation, and via donor-selection they can express various genotypes of interest for better disease modeling. Furthermore, drug screenings and toxicological screenings in hESC and hiPSC are more pertinent to identify drugs or chemical compounds that are harmful for human, than a mouse model could predict. Despite continuing research in the wide field of therapeutic applications, further understanding of the underlying basic mechanisms of stem cell function is necessary. Here, we summarize current knowledge concerning pluripotency, self-renewal, apoptosis, motility, epithelial-to-mesenchymal transition and differentiation of pluripotent stem cells.

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Clinical Trials in a Dish: The Potential of Pluripotent Stem Cells to Develop Therapies for Neurodegenerative Diseases

Cited by 74 publications

References 147 publications

Three-dimensional hyaluronic acid hydrogel-based models for in vitro human iPSC-derived NPC culture and differentiation

Three-dimensional hyaluronic acid hydrogel-based models for in vitro human iPSC-derived NPC culture and differentiation

Modeling the autistic cell: iPSCs recapitulate developmental principles of syndromic and nonsyndromic ASD

Full biological characterization of human pluripotent stem cells will open the door to translational research

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