Abstract
Reversine or 2-(4-morpholinoanilino)-N6-cyclohexyladenine was originally identified as a small organic molecule that induces dedifferentiation of lineage-committed mouse myoblasts, C2C12, and redirects them into lipocytes or osteoblasts under lineage-specific conditions (LISCs). Further, it was proven that this small molecule can induce cell cycle arrest and apoptosis and thus selectively lead cancer cells to cell death. Further studies demonstrated that reversine, and more specifically the C2 position of the purine ring, can tolerate a wide range of substitutions without activity loss. In this study, a piperazine analog of reversine, also known as aza-reversine, and a biotinylated derivative of aza-reversine were synthesized, and their potential medical applications were investigated by transforming the endoderm originates fetal lung cells (MRC-5) into the mesoderm originated osteoblasts and by differentiating mesenchymal cells into osteoblasts. Moreover, the reprogramming capacity of aza-reversine and biotinylated aza-reversine was investigated against MRC-5 cells and mesenchymal cells after the immobilization on PMMA/HEMA polymeric surfaces. The results showed that both aza-reversine and the biofunctionalized, biotinylated analog induced the reprogramming of MRC-5 cells to a more primitive, pluripotent state and can further transform them into osteoblasts under osteogenic culture conditions. These molecules also induced the differentiation of dental and adipose mesenchymal cells to osteoblasts. Thus, the possibility to load a small molecule with useful “information” for delivering that into specific cell targets opens new therapeutic personalized applications.
Highlights
Stem cells are unique cells that are able to self-renew and differentiate into specific cell types under proper conditions
Reversine was identified as a novel dedifferentiation factor of lineage-committed mouse myoblasts C2C12, which were redirected into lipocytes or osteoblasts, under lineage-specific conditions (LISCs) [6]
Lineagecommitted annulus fibrosus cells dedifferentiated into progenitor-like cells after treatment with reversine [10] and porcine muscle-derived stem cells (PMDSCs) were transformed into female germ-like cells based on the reports of Saraiya and Lv, respectively [11]
Summary
Stem cells are unique cells that are able to self-renew and differentiate into specific cell types under proper conditions Their key role in cellular processes during embryonic development and tissue homeostasis stem cells offer great potential in the treatment of various diseases, including type I diabetes [1,2], muscular dystrophies, bone diseases, cancer, neurodegenerative and cardiovascular [3] disorders [4]. According to Anastasia and coworkers, reversine was able to transform primary murine and human dermal fibroblasts into myogenic-competent cells in vitro and in vivo [7] It induced adipocyte differentiation in 3T3-L1 cells [8] and increased the plasticity of C2C12 myoblasts towards the neuroectodermal line [9]. Further studies revealed that reversine can be employed as a dedifferentiation factor and for the enhancement of the differentiation ability of mesenchymal stem cells [12]
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