iPSCs and small molecules: a reciprocal effort towards better approaches for drug discovery

Abstract

The revolutionary induced pluripotent stem cell (iPSC) technology provides a new path for cell replacement therapies and drug screening. Patient-specific iPSCs and subsequent differentiated cells manifesting disease phenotypes will finally position human disease pathology at the core of drug discovery. Cells used to test the toxic effects of drugs can also be generated from normal iPSCs and provide a much more accurate and cost-effective system than many animal models. Here, we highlight the recent progress in iPSC-based cell therapy, disease modeling and drug evaluations. In addition, we discuss the use of small molecule drugs to improve the generation of iPSCs and understand the reprogramming mechanism. It is foreseeable that the interplay between iPSC technology and small molecule compounds will push forward the applications of iPSC-based therapy and screening systems in the real world and eventually revolutionize the methods used to treat diseases.

Lithium chloride improves the efficiency of induced pluripotent stem cell-derived neurospheres

“…Likewise, noggin induces the progressive neural patterning of iPSCs after which the propagation of iPSC-derived colonies in a suspension medium containing neural basal medium (NBM) supplemented with basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) induces their aggregation and formation of spherical-like clusters termed neurospheres. At the neurosphere stage, the efficient generation and expansion of NSCs/NPCs is taking place ( Frisca et al, 2013 ), consisting of a heterogeneous population of NSCs ( Valenzuela et al, 2007 ) with a reduced risk of tumor formation after transplantation ( Yuan et al, 2013 ;Zhang et al, 2013 ).…”

Use of induced pluripotent stem cells (iPSCs) and cerebral organoids in modeling the congenital infection and neuropathogenesis induced by Zika virus

“…Studies using tissue from autopsies may offer a great indicator of structural changes in the brain at the cellular and molecular level. The fact that about 90% of the drugs approved in such experimental models are no longer rejected due to efficacy failures or unexpected discovery of toxicity at the clinical trial stage confirms the importance of human tissues in such studies . The models of diseases that faithfully represent actual human diseases and their physiological peculiarities are needed to improve the success rate of newly discovered drugs …”

Methods of induced pluripotent stem cells for clinical application

“…These protein-based methods are also attractive for clinical application because of the absence of breaks in existing host genes and the reactivation of transgenes; however, the generation efficiencies remain lower compared to those in the existing retrovirus systems [50,51] . Finally, small-molecule drugs have been investigated for establishing safe methods of iPSC generation for clinical application because they are nonimmunogenic, cost-effective, and easy to handle [52] . Recently, successful reprogramming of mouse somatic cells without transgene introduction was achieved with small-molecule drug combinations [53] .…”