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Small molecule epigenetic modifiers combined with cell signalling modulators as a promising cell reprogramming strategy


Alexanian Arshak



       Recent achievements of cellular reprogramming have enabled the generation of induced pluripotent stem cells or other lineage-committed cells from more accessible and abundant somatic cell types by defined genetic factors. However, serious concerns remain about the efficiency and safety of current genetic approaches.

Recent studies showed that cell reprogramming can also be achieved purely by chemical approach (small molecule approach). Generation of induced pluripotent cells or trans-differentiation of one cell type to another had been achieved by biologically active small molecules that are involved in the regulation of the modulators of epigenetic machinery and specific cell signaling pathways.

Recently, using this cell reprogramming strategy we have been able to turn human mesenchymal stem cells directly into neuronal progenitors that have the potential to generate different neuronal subtypes, such as dopaminergic, cholinergic, and GABAergic cells when further grown in appropriate neuronal differentiation media (Fig.1).

We also demonstrated that this approach can be used to manipulate the fate of Cancer cells. Our studies showed that glioblastoma cell completely eradicated when exposed to specific combinations of epigenetic modulators (Fig.2). Interestingly, small percentage of glioblastoma cells differentiated into neuronal-like cells when epigenetic modifiers combined with specific modulators of cell signaling pathways that promote neural differentiation.



All these data (ours and others) suggest that the specific combinations of epigenetic modifiers  can reactivate or enhance the plasticity of adult somatic cells (stem/progenitor cells or mature differentiated cells) which at appropriate environmental signals can be converted into more immature cell stages with wider differentiation potential or directly turned into other cell types. These data also showed, that similar to the normal somatic cells, cancer cells fate can also be changed with similar cell reprogramming approach. With further advances in understanding the major mechanisms in epigenetic regulation and development of new specific chemical tools for their regulation will open new exciting perspectives not only for regenerative medicine but also for cancer treatments. 


 Alexanian Arshak is currently the Chief Scientific Officer at Cell Reprogramming & Therapeutics LLC and an Adjunct Associate Professor in the Department of Medicine at the Medical College of Wisconsin (MCW). Previously, he held faculty positions in the Departments of Neurosurgery at MCW (2000-2013) and in the Departments of Anatomy and Neurobiology, as well as in Biochemistry and Molecular Biology, at Colorado State University (1997-2000). He has received training at universities and centers worldwide, including the Pasteur Institute and University of Montpelier in France, University of Saarland in Germany, Institute of Biochemistry in China and Russia, and Colorado State University. His research funded by the governmental grants such as NIH and Veterans Affairs, as well as other organizations such as Spinal Cord Society, Quadracci, Bryon Riesch Paralysis Foundation, AOSpine North America and International, Hansjorg Wyss and others. The areas of interest of his research are the epigenetic regulation of cell fate commitment and differentiation, development of cell reprogramming technologies to produce different neuronal and glial cell types, and elucidation of the therapeutic effect of these specialized cell types in several neurological disorders.

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