Impact of the Epigenetically Regulated Hoxa-5 Gene in Neural Differentiation from Human Adipose-Derived Stem Cells

Overview

Journal Biology (Basel)

Publisher MDPI

Specialty Biology

Date 2021 Aug 27

PMID 34440035

Citations 2

Authors

Rosa Hernandez

Cristina Jimenez-Luna

Raul Ortiz

Fernando Setien

Miguel Lopez

Gloria Perazzoli

Manel Esteller

Maria Berdasco

Jose Prados

Consolacion Melguizo

Affiliations

Soon will be listed here.

Abstract

Human adipose-derived mesenchymal stem cells (hASCs) may be used in some nervous system pathologies, although obtaining an adequate degree of neuronal differentiation is an important barrier to their applicability. This requires a deep understanding of the expression and epigenetic changes of the most important genes involved in their differentiation. We used hASCs from human lipoaspirates to induce neuronal-like cells through three protocols (Neu1, 2, and 3), determined the degree of neuronal differentiation using specific biomarkers in culture cells and neurospheres, and analyzed epigenetic changes of genes involved in this differentiation. Furthermore, we selected the gene to determine its potential to improve neuronal differentiation. Our results showed that an excellent hASC neuronal differentiation process using Neu1 which efficiently modulated NES, CHAT, SNAP25, or SCN9A neuronal marker expression. In addition, epigenetic studies showed relevant changes in , , , , , and genes. Functional studies of the gene using CRISPR/dCas9 and lentiviral systems showed that its overexpression induced hASCs neuronal differentiation that was accelerated with the exposure to Neu1. These results suggest that is an essential gene in hASCs neuronal differentiation and therefore, a potential candidate for the development of cell therapy strategies in neurological disorders.

Citing Articles

The circular RNA promotes transcription by recruiting Kat7 and leading to increased expression, which inhibits neuronal apoptosis in acute ischemic stroke.

Zhang F, Zhang L, Zhao L, Lu Y, Dong X, Liu Y Neural Regen Res. 2023; 18(10):2237-2245.

PMID: 37056143 PMC: 10328278. DOI: 10.4103/1673-5374.369115.

Comprehensive Landscape of HOXA2, HOXA9, and HOXA10 as Potential Biomarkers for Predicting Progression and Prognosis in Prostate Cancer.

Song Y, Xian P, Luo H, Dai J, Bai Y, Li Y J Immunol Res. 2022; 2022:5740971.

PMID: 35372588 PMC: 8970952. DOI: 10.1155/2022/5740971.

References

Gong L, Cao L, Shen Z, Shao L, Gao S, Zhang C . Materials for Neural Differentiation, Trans-Differentiation, and Modeling of Neurological Disease. Adv Mater. 2018; 30(17):e1705684. DOI: 10.1002/adma.201705684. View

Cano-Rodriguez D, Gjaltema R, Jilderda L, Jellema P, Dokter-Fokkens J, Ruiters M . Writing of H3K4Me3 overcomes epigenetic silencing in a sustained but context-dependent manner. Nat Commun. 2016; 7:12284. PMC: 4987519. DOI: 10.1038/ncomms12284. View

Mortada I, Mortada R . Epigenetic changes in mesenchymal stem cells differentiation. Eur J Med Genet. 2017; 61(2):114-118. DOI: 10.1016/j.ejmg.2017.10.015. View

Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I . Controlling the false discovery rate in behavior genetics research. Behav Brain Res. 2001; 125(1-2):279-84. DOI: 10.1016/s0166-4328(01)00297-2. View

Jaenisch R, Bird A . Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003; 33 Suppl:245-54. DOI: 10.1038/ng1089. View

Alexanian A . Epigenetic modulators promote mesenchymal stem cell phenotype switches. Int J Biochem Cell Biol. 2015; 64:190-4. DOI: 10.1016/j.biocel.2015.04.010. View

Deng J, Petersen B, Steindler D, Jorgensen M, Laywell E . Mesenchymal stem cells spontaneously express neural proteins in culture and are neurogenic after transplantation. Stem Cells. 2005; 24(4):1054-64. DOI: 10.1634/stemcells.2005-0370. View

Turac G, Duruksu G, Karaoz E . The Effect of Recombinant Tyrosine Hydroxylase Expression on the Neurogenic Differentiation Potency of Mesenchymal Stem Cells. Neurospine. 2018; 15(1):42-53. PMC: 5944638. DOI: 10.14245/ns.1836010.005. View

Bossolasco P, Cova L, Calzarossa C, Rimoldi S, Borsotti C, Lambertenghi Deliliers G . Neuro-glial differentiation of human bone marrow stem cells in vitro. Exp Neurol. 2005; 193(2):312-25. DOI: 10.1016/j.expneurol.2004.12.013. View

10.

Chudickova M, Bruza P, Zajicova A, Trosan P, Svobodova L, Javorkova E . Targeted neural differentiation of murine mesenchymal stem cells by a protocol simulating the inflammatory site of neural injury. J Tissue Eng Regen Med. 2015; 11(5):1588-1597. DOI: 10.1002/term.2059. View

11.

Maeder M, Linder S, Cascio V, Fu Y, Ho Q, Joung J . CRISPR RNA-guided activation of endogenous human genes. Nat Methods. 2013; 10(10):977-9. PMC: 3794058. DOI: 10.1038/nmeth.2598. View

12.

Urrutia D, Caviedes P, Mardones R, Minguell J, Vega-Letter A, Jofre C . Comparative study of the neural differentiation capacity of mesenchymal stromal cells from different tissue sources: An approach for their use in neural regeneration therapies. PLoS One. 2019; 14(3):e0213032. PMC: 6437714. DOI: 10.1371/journal.pone.0213032. View

13.

Fila-Danilow A, Borkowska P, Paul-Samojedny M, Kowalczyk M, Kowalski J . The influence of TSA and VPA on the in vitro differentiation of bone marrow mesenchymal stem cells into neuronal lineage cells: Gene expression studies. Postepy Hig Med Dosw (Online). 2017; 71(0):236-242. DOI: 10.5604/01.3001.0010.3809. View

14.

Yang E, Liu N, Tang Y, Hu Y, Zhang P, Pan C . Generation of neurospheres from human adipose-derived stem cells. Biomed Res Int. 2015; 2015:743714. PMC: 4357140. DOI: 10.1155/2015/743714. View

15.

Wang M, Qiu Y, Cai M, Zhang C, Wang X, Liu H . Role and molecular mechanism of stem cells in colorectal cancer initiation. J Drug Target. 2019; 28(1):1-10. DOI: 10.1080/1061186X.2019.1632317. View

16.

Aryee M, Jaffe A, Corrada-Bravo H, Ladd-Acosta C, Feinberg A, Hansen K . Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics. 2014; 30(10):1363-9. PMC: 4016708. DOI: 10.1093/bioinformatics/btu049. View

17.

Bae K, Park J, Kim H, Kim D, Park D, Kang S . Neuron-like differentiation of bone marrow-derived mesenchymal stem cells. Yonsei Med J. 2011; 52(3):401-12. PMC: 3101055. DOI: 10.3349/ymj.2011.52.3.401. View

18.

Dave S, Patel C, Vanikar A, Trivedi H . differentiation of neural cells from human adipose tissue derived stromal cells. Neurol India. 2018; 66(3):716-721. DOI: 10.4103/0028-3886.232326. View

19.

Marei H, El-Gamal A, Althani A, Afifi N, Abd-Elmaksoud A, Farag A . Cholinergic and dopaminergic neuronal differentiation of human adipose tissue derived mesenchymal stem cells. J Cell Physiol. 2017; 233(2):936-945. DOI: 10.1002/jcp.25937. View

20.

Tondreau T, Dejeneffe M, Meuleman N, Stamatopoulos B, Delforge A, Martiat P . Gene expression pattern of functional neuronal cells derived from human bone marrow mesenchymal stromal cells. BMC Genomics. 2008; 9:166. PMC: 2358905. DOI: 10.1186/1471-2164-9-166. View