Chemical compound-based direct reprogramming for future clinical applications

Abstract

Recent studies have revealed that a combination of chemical compounds enables direct reprogramming from one somatic cell type into another without the use of transgenes by regulating cellular signaling pathways and epigenetic modifications. The generation of induced pluripotent stem (iPS) cells generally requires virus vector-mediated expression of multiple transcription factors, which might disrupt genomic integrity and proper cell functions. The direct reprogramming is a promising alternative to rapidly prepare different cell types by bypassing the pluripotent state. Because the strategy also depends on forced expression of exogenous lineage-specific transcription factors, the direct reprogramming in a chemical compound-based manner is an ideal approach to further reduce the risk for tumorigenesis. So far, a number of reported research efforts have revealed that combinations of chemical compounds and cell-type specific medium transdifferentiate somatic cells into desired cell types including neuronal cells, glial cells, neural stem cells, brown adipocytes, cardiomyocytes, somatic progenitor cells, and pluripotent stem cells. These desired cells rapidly converted from patient-derived autologous fibroblasts can be applied for their own transplantation therapy to avoid immune rejection. However, complete chemical compound-induced conversions remain challenging particularly in adult human-derived fibroblasts compared with mouse embryonic fibroblasts (MEFs). This review summarizes up-to-date progress in each specific cell type and discusses prospects for future clinical application toward cell transplantation therapy.

Direct conversion of fibroblasts to osteoblasts as a novel strategy for bone regeneration in elderly individuals

“…The increase in gene copy numbers with pluripotency and cell proliferation enhances the risk of oncogenesis 75,76 . There is, however, less risk of such mutations with direct reprogramming because this process can take place in the absence of cell proliferation 77,78 . In addition, the proliferation of iPSCs in the uncontrolled state is similar to that of cancerous cells 79 .…”

GSK‑3 inhibitor CHIR99021 enriches glioma stem‑like cells

“…CHIR99021 is a chemical compound that acts as an inhibitor of GSK-3. It has been demonstrated to be useful for applications in molecular biology for transforming the cell type into induced pluripotent stem cells (iPSCs) and neurons (13,14). However, there is no evidence that CHIR99021 can transform primary low-grade glioma cells into GSLCs.…”

Cancer cell reprogramming: a promising therapy converting malignancy to benignity

“…Small molecules can also serve as an excellent candidate to efficiently regulate cellular processes via directly targeting signaling pathways such as the Wnt, Hedgehog, and Hippo pathways [91–93]. It is convenient to manufacture small molecules and scale their throughput to induce reprogramming with different lineages [94]. Moreover, such molecules can be utilized as molecular probes to investigate the underlying changes in molecular signaling during cancer cell reprogramming, which might lead to an improvement in reprogramming efficiency and reduction of the off-target effect [94].…”

“…It is convenient to manufacture small molecules and scale their throughput to induce reprogramming with different lineages [94]. Moreover, such molecules can be utilized as molecular probes to investigate the underlying changes in molecular signaling during cancer cell reprogramming, which might lead to an improvement in reprogramming efficiency and reduction of the off-target effect [94]. For small molecule-mediated cancer cell reprogramming to succeed, it is necessary to identify and develop small biochemical molecules that can assist cancer cells in overcoming the epigenetic barriers and blockades in various cellular signaling pathways [88, 89].…”