Chemical Approaches to Stem Cell Biology and Therapeutics

Li, Wenlin; Li, Ké; Wei, Wanguo; Ding, Sheng

doi:10.1016/j.stem.2013.08.002

Cited by 158 publications

(139 citation statements)

References 118 publications

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“…Small molecules often provide reversible, temporal effects that can be finely tuned by their combination and concentrations. To date, a number of studies have identified several compounds that can enhance cell reprogramming and replace transcription factor-based reprogramming Li et al, 2012Li et al, , 2013Shi et al, 2008). These studies have used compounds that target cellular activities ranging from cytoplasmic signaling and cell cycle control to histone and DNA modification (for review, see Li et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Prolonged Proteasome Inhibition Cyclically Upregulates Oct3/4 and Nanog Gene Expression, but Reduces Induced Pluripotent Stem Cell Colony Formation

Elizabeth

StaszkiewiczJaroslaw

PowerRachel

et al. 2015

Cellular Reprogramming

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There is ample evidence that the ubiquitin-proteasome system is an important regulator of transcription and its activity is necessary for maintaining pluripotency and promoting cellular reprogramming. Moreover, proteasome activity contributes to maintaining the open chromatin structure found in pluripotent stem cells, acting as a transcriptional inhibitor at specific gene loci generally associated with differentiation. The current study was designed to understand further the role of proteasome inhibition in reprogramming and its ability to modulate endogenous expression of pluripotency-related genes and induced pluripotent stem cells (iPSCs) colony formation. Herein, we demonstrate that acute combinatorial treatment with the proteasome inhibitors MG101 or MG132 and the histone deacetylase (HDAC) inhibitor valproic acid (VPA) increases gene expression of the pluripotency marker Oct3/4, and that MG101 alone is as effective as VPA in the induction of Oct3/4 mRNA expression in fibroblasts. Prolonged proteasome inhibition cyclically upregulates gene expression of Oct3/4 and Nanog, but reduces colony formation in the presence of the iPSC induction cocktail. In conclusion, our results demonstrate that the 26S proteasome is an essential modulator in the reprogramming process. Its inhibition enhances expression of pluripotency-related genes; however, efficient colony formation requires proteasome activity. Therefore, discovery of small molecules that increase proteasome activity might lead to more efficient cell reprogramming and generation of pluripotent cells.

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Section: Discussionmentioning

confidence: 99%

Prolonged Proteasome Inhibition Cyclically Upregulates Oct3/4 and Nanog Gene Expression, but Reduces Induced Pluripotent Stem Cell Colony Formation

Elizabeth

StaszkiewiczJaroslaw

PowerRachel

et al. 2015

Cellular Reprogramming

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“…Protocols are needed that result in cells with adult-like functionality [65]. The investigation of signalling pathways controlling cell development has led to successful strategies to direct stem cell fate [306], and small molecules have been utilised for the creation of differentiation protocols [202,203,307,308]. In addition, bioreactors have been successfully employed to direct stem cell fate [288,295].…”

Section: Hydrostatic Pressure Bioreactormentioning

confidence: 99%

Pluripotent Stem Cells and Their Dynamic Niche

Reinwald¹,

Bratt²,

Haj³

2016

Pluripotent Stem Cells - From the Bench to the Clinic

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Cell-seeded implants are a regenerative medicine strategy that aims to replace injured tissue and restore tissue function. Pluripotent stem cells are promising cell candidates for the development of regenerative medicine therapies as they have the ability to selfrenew and commit towards numerous cell types. In vivo, stem cells reside in a dynamic niche, a stem cell-specific microenvironment that possesses chemical, biological and mechanical cues, which drive the stem cell fate and renewal. The connection between stem cells and their niche is a two-way relationship consisting of both cell-cell interaction and cell-extracellular matrix (ECM) interactions. An alternative regenerative medicine approach is the manipulation of the stem cell microenvironment. Hence, novel strategies have been developed including 3D biomaterials and bioreactor technologies providing topographical, chemical and mechanical cues to recreate the stem cell niche. Understanding the mechanisms controlling stem cell fate and the dynamic nature of the stem cell niche will enable researchers to replicate this stem cell-specific microenvironment, and therefore, harness and control the valuable attributes which stem cells possess. This chapter elucidates the importance of pluripotent stem cells and their dynamic niche in regenerative medicine. It further presents novel strategies to replicate chemical, topographical and mechanical stimuli which are essential for the regulation of stem cell fate and hence tissue regeneration.

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“…Although these above approaches have made groundbreaking success in cell reprogramming, the involvement of oncogenic TFs and genetic modifications imposes clinically unacceptable risks such as inevitably harboring safety, efficiency, and other technical issues resulting from genetic manipulations [138]. In contrast, a number of small molecules and their combinations, targeting specific signaling pathways and mechanisms, are more convenient to handle, faster, and potentially safer to regulate protein functions responsible for reprogramming than genetic manipulation [139]. Importantly, effects of small molecules are typically rapid and reversible and can be fine tuned by varying concentrations and combinations of small molecules [139].…”

Section: Small Chemical Moleculesmentioning

confidence: 99%

Therapeutical Strategies for Spinal Cord Injury and a Promising Autologous Astrocyte-Based Therapy Using Efficient Reprogramming Techniques

et al. 2015

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Spinal cord injury (SCI) is a traumatic event resulting in disturbances to normal sensory, motor, or autonomic functions, which ultimately impacts a patient's physical, psychological, and social well-being. Until now, no available therapy for SCI can effectively slow down or halt the disease progression. Compared to traditional treatments, e.g., medication, surgery, and functional electrical stimulation, stem cell replacement therapy shows high potential for repair and functional plasticity. Thus, stem cell therapy may provide a promising strategy in curative treatment of SCI, specifically when considering the requirement of neuron replenishment in the spinal cord after distinct acute injuries. However, the therapeutic application of neural stem cells (NSCs) still faces enormous challenges, such as ethical issues, possible inflammatory reactions, graft rejection, and tumor formation. Therefore, it is of vital interest to identify more suitable sources of cells with stem cell potential, which might potentially be harnessed for local neural repair. Due to abovementioned possible drawbacks, these cells should be autologous. Reprogramming of astrocytes to generate the desired neuronal cell types would open the door to autologous cell transplantation and treatment of SCI without possible severe side effects. In this paper, we review the relevant therapeutic strategies for SCI, and conversion of astrocyte into NSCs, suggesting this procedure as a possible treatment option.

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Chemical Approaches to Stem Cell Biology and Therapeutics

Cited by 158 publications

References 118 publications

Prolonged Proteasome Inhibition Cyclically Upregulates Oct3/4 and Nanog Gene Expression, but Reduces Induced Pluripotent Stem Cell Colony Formation

Prolonged Proteasome Inhibition Cyclically Upregulates Oct3/4 and Nanog Gene Expression, but Reduces Induced Pluripotent Stem Cell Colony Formation

Pluripotent Stem Cells and Their Dynamic Niche

Therapeutical Strategies for Spinal Cord Injury and a Promising Autologous Astrocyte-Based Therapy Using Efficient Reprogramming Techniques

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