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Liu Y.,University of Texas Health Science Center at Houston | Deng W.,University of California at Davis | Deng W.,Institute for Pediatric Regenerative Medicine
Brain Research | Year: 2016

With the technology of reprogramming somatic cells by introducing defined transcription factors that enables the generation of induced pluripotent stem cells(iPSCs) with pluripotency comparable to that of embryonic stem cells (ESCs),it has become possible to use this technology to produce various cell sand tissues that have been difficult to obtain from living bodies.This advancement is bringing for thrapid progress in iPSC-based disease modeling, drugs creening,and regenerative medicine.More and more studies have demonstrated that phenotypes of adult-on set neurodegenerative disorders could be rather faith fully recapitulated in iPSC-derived neural cell cultures.More over,despite the adult- on set nature of the diseases,pathogenicphe notypes and cellular abnormalities of tenexist in early developmental stages,providing new windows of opportunity for understanding mechanisms underlying neurodegenerative disorders and for discovering new medicines. The cell reprogramming technology enable a reverse engineering approach for modeling the cellular degenerative phenotypes of a wide range of human disorders. An excellent example is the study of the human neurodegenerative disease amyotrophic lateral sclerosis (ALS) using iPSCs. ALS is a progressive neurodegenerative disease characterized by the loss of upper and lower motor neurons (MNs), culminating in muscle wasting and death from respiratory failure. The iPSC approach provides innovative cell culture plat- forms to serve as ALS patient-derived model systems. Researchers have converted iPSCs derived from ALS patients into MNs and various types of glial cells, all of which are involved in ALS, to study the disease. The iPSC technology could be used to determine the role ofspecific genetic factors to track down what'swrong in the neurodegenerative disease process in the disease-in-a-dish model. Mean while,parallel experiments of targeting the same specific genes in human ESCs couldal so be performed to control and to complement the iPSC-based approach for ALS disease modeling studies. © 2015 Elsevier B.V.

Zhang J.,University of California at Davis | Zhang J.,Chongqing Medical University | Calafiore M.,University of California at Davis | Zeng Q.,University of California at Davis | And 8 more authors.
Stem Cell Reviews and Reports | Year: 2011

A major road-block in stem cell therapy is the poor homing and integration of transplanted stem cells with the targeted host tissue. Human induced pluripotent stem (hiPS) cells are considered an excellent alternative to embryonic stem (ES) cells and we tested the feasibility of using small, physiological electric fields (EFs) to guide hiPS cells to their target. Applied EFs stimulated and guided migration of cultured hiPS cells toward the anode, with a stimulation threshold of <30 mV/mm; in three-dimensional (3D) culture hiPS cells remained stationary, whereas in an applied EF they migrated directionally. This is of significance as the therapeutic use of hiPS cells occurs in a 3D environment. EF exposure did not alter expression of the pluripotency markers SSEA-4 and Oct-4 in hiPS cells. We compared EF-directed migration (galvanotaxis) of hiPS cells and hES cells and found that hiPS cells showed greater sensitivity and directedness than those of hES cells in an EF, while hES cells migrated toward cathode. Rho-kinase (ROCK) inhibition, a method to aid expansion and survival of stem cells, significantly increased the motility, but reduced directionality of iPS cells in an EF by 70-80%. Thus, our study has revealed that physiological EF is an effective guidance cue for the migration of hiPS cells in either 2D or 3D environments and that will occur in a ROCK-dependent manner. Our current finding may lead to techniques for applying EFs in vivo to guide migration of transplanted stem cells. © 2011 The Author(s).

Choe Y.,University of California at San Francisco | Zarbalis K.S.,University of California at Davis | Zarbalis K.S.,Institute for Pediatric Regenerative Medicine | Pleasure S.J.,University of California at San Francisco
PLoS ONE | Year: 2014

Embryonic neural crest cells contribute to the development of the craniofacial mesenchyme, forebrain meninges and perivascular cells. In this study, we investigated the function of β-catenin signaling in neural crest cells abutting the dorsal forebrain during development. In the absence of β-catenin signaling, neural crest cells failed to expand in the interhemispheric region and produced ectopic smooth muscle cells instead of generating dermal and calvarial mesenchyme. In contrast, constitutive expression of stabilized β-catenin in neural crest cells increased the number of mesenchymal lineage precursors suggesting that β-catenin signaling is necessary for the expansion of neural crest-derived mesenchymal cells. Interestingly, the loss of neural crest-derived mesenchymal stem cells (MSCs) leads to failure of telencephalic midline invagination and causes ventricular system defects. This study shows that β-catenin signaling is required for the switch of neural crest cells to MSCs and mediates the expansion of MSCs to drive the formation of mesenchymal structures of the head. Furthermore, loss of these structures causes striking defects in forebrain morphogenesis. © 2014 Choe et al.

Biswas D.,Institute for Pediatric Regenerative Medicine | Jiang P.,Institute for Pediatric Regenerative Medicine | Jiang P.,University of Nebraska Medical Center
International Journal of Molecular Sciences | Year: 2016

The ability to generate transplantable neural cells in a large quantity in the laboratory is a critical step in the field of developing stem cell regenerative medicine for neural repair. During the last few years, groundbreaking studies have shown that cell fate of adult somatic cells can be reprogrammed through lineage specific expression of transcription factors (TFs)-and defined culture conditions. This key concept has been used to identify a number of potent small molecules that could enhance the efficiency of reprogramming with TFs. Recently, a growing number of studies have shown that small molecules targeting specific epigenetic and signaling pathways can replace all of the reprogramming TFs. Here, we provide a detailed review of the studies reporting the generation of chemically induced pluripotent stem cells (ciPSCs), neural stem cells (ciNSCs), and neurons (ciN). We also discuss the main mechanisms of actions and the pathways that the small molecules regulate during chemical reprogramming. © 2016 by the authors; licensee MDPI, Basel, Switzerland.

Liu Y.,University of California at San Diego | Liu Y.,Scripps Research Institute | Jiang P.,University of California at Davis | Jiang P.,Institute for Pediatric Regenerative Medicine | And 2 more authors.
Nature Protocols | Year: 2011

Pluripotent stem cells can be genetically labeled to facilitate differentiation studies. In this paper, we describe a gene-targeting protocol to knock in a GFP cassette into key gene loci in human pluripotent stem cells (hPSCs), and then use the genetically tagged hPSCs to guide in vitro differentiation, immunocytochemical and electrophysiological profiling and in vivo characterization after cell transplantation. The Olig transcription factors have key roles in the transcription regulatory pathways for the genesis of motor neurons (MNs) and oligodendrocytes (OLs). We have generated OLIG2-GFP hPSC reporter lines that reliably mark MNs and OLs for monitoring their sequential differentiation from hPSCs. The expression of the GFP reporter recapitulates the endogenous expression of OLIG genes. The in vitro characterization of fluorescence-activated cell sorting-purified cells is consistent with cells of the MN or OL lineages, depending on the stages at which they are collected. This protocol is efficient and reliable and usually takes 5-7 months to complete. The genetic tagging-differentiation methodology used herein provides a general framework for similar work for differentiation of hPSCs into other lineages. © 2011 Nature America, Inc. All rights reserved.

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