Functional Network Reconstruction Reveals Somatic Stemness Genetic Maps and Dedifferentiation-Like Transcriptome Reprogramming Induced by GATA2

¹ Institute of Microbiology and Immunology, National Yang-Ming University
² VGH-YM Genome Center, National Yang-Ming University
³ Department of Orthopedics, Taipei City Hospital, Taipei, Taiwan
⁴ Institute of Clinical Medicine, National Yang-Ming University; Department of Medical Research and Education, Taipei Veterans General Hospital, Taiwan
⁵ Finnish Red Cross Blood Service, Helsinki, Finland
⁶ Institute of Oral Biology, National Yang-Ming University; Department of Medical Research and Education, Taipei Veterans General Hospital, Taiwan
⁷ Institute of Microbiology and Immunology, VGH-YM Genome Center, National Yang-Ming University; Department of Education and Research, Taipei City Hospital, Taipei, Taiwan

^* To whom correspondence should be addressed. E-mail: hwwang{at}ym.edu.tw.

	Abstract

Somatic stem cells transplantation holds great promises in regenerative medicine. The best-characterized adult stem cells are mesenchymal stem cells (MSCs), neural stem cells (NSCs) and CD133⁺ hematopoietic stem cells (HSCs). The applications of HSCs are hampered since they are difficult to maintain in un-differentiated state in vitro. Understanding genes responsible for stem cell properties and their interactions will help on this issue. The construction of stem cell genetic networks will also help to develop rational strategies to revert somatic cells back to a stem-like state. We performed a systemic study on human CD133⁺ HSCs, NSCs, MSCs, embryonic stem cells, and 2 different progenies of CD133⁺ HSCs: microvascular endothelial cells (MVECs) and peripheral blood mononuclear cells. Genes abundant in each or in all 3 somatic stem cells were identified. We also observed complex genetic networks functioning in post-natal stem cells, in which several genes such as PTPN11 and DHFR acted as hubs to maintain the stability and connectivity of the whole genetic network. 87 HSC genes, including ANGPT1 and GATA2, were independently identified by comparing CD34⁺CD33^-CD38^- hematopoietic stem cells with CD34⁺ precursors and various matured progenies. Introducing GATA2 into MVECs resulted in dedifferentiation-like transcriptome reprogramming, with HSC genes (such as ANGPT1) being up while endothelial genes (such as EPHB2) being down. This study provides a foundation for a more detailed understanding of human somatic stem cells. Expressing the newly discovered stem cell genes in matured cells might lead to a global reversion of somatic transcriptome to a stem-like status.