A Phenotypic Switch of Differentiated Glial Cells to Dedifferentiated Cells Is Regulated by Folate Receptor α

• Published in: Stem cells (Dayton, Ohio) Ohio), 2019-11, Vol.37 (11), p.1441-1454
• Main Authors: Monick, Sarah, Mohanty, Vineet, Khan, Mariam, Yerneni, Gowtham, Kumar, Raj, Cantu, Jorge, Ichi, Shunsuke, Xi, Guifa, Singh, Bal Ram, Tomita, Tadanori, Mayanil, Chandra Shekhar
• Format: Article
• Language: English
• Subjects: Acetylation; Cell differentiation; Chromatin remodeling; Cranial neural crest cells; Dedifferentiation; Differentiation; Folate receptor alpha; Folic acid; Glial cells; KLF4 protein; Nuclear transport; Oct-4 protein; Oct4; Phosphorylation; Pluripotency; Sox2; Stem cells; Tissue‐Specific Stem Cells; Translocation; Vitamin B
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.3067

In a previous study, we showed that folate receptor‐α (FRα) translocates to the nucleus where it acts as a transcription factor and upregulates Hes1, Oct4, Sox2, and Klf4 genes responsible for pluripotency. Here, we show that acetylation and phosphorylation of FRα favor its nuclear translocation in the presence of folate and can cause a phenotypic switch from differentiated glial cells to dedifferentiated cells. shRNA‐FRα mediated knockdown of FRα was used to confirm the role of FRα in dedifferentiation. Ocimum sanctum hydrophilic fraction‐1 treatment not only blocks the folate mediated dedifferentiation of glial cells but also promotes redifferentiation of dedifferentiated glial cells, possibly by reducing the nuclear translocation of ~38 kDa FRα and subsequent interaction with chromatin assembly factor‐1. Stem Cells 2019;37:1441–1454 Possible mechanisms by which Ocimum sanctum hydrophilic fraction‐1 prevents the formation of folate receptor‐α complex are: (a) the caffeoylquinic acid component of O. sanctum hydrophilic fraction‐1 presumably decreases acetylation of folate receptor‐α by decreasing the acetyl transferase or increasing the deacetylases activity, and subsequent nuclear translocation, and (b) since nuclear folate receptor‐α binds to chromatin assembly factor‐1 in folate‐induced dedifferentiated cells and not in differentiated glial cells, the reduction of folate receptor‐α in the nucleus by O. sanctum hydrophilic fraction‐1 may reactivate chromatin assembly factor‐1 and favor differentiation.