Functional network reconstruction reveals somatic stemness genetic maps and dedifferentiation-like transcriptome reprogramming induced by GATA2.
Somatic stem cell transplantation holds great promise 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 these cells are difficult to maintain in an undifferentiated 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, and embryonic stem cells and two different progenies of CD133(+) HSCs, microvascular endothelial cells (MVECs) and peripheral blood mononuclear cells. Genes abundant in each or in all three somatic stem cells were identified. We also observed complex genetic networks functioning in postnatal 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. Eighty-seven 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 and 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.
Huang
Tse-Shun
TS
Institute of Microbiology and Immunology, National Yang-Ming University, No. 155, Sec 2, Li-Nong Street, Taipei 112, Taiwan.
Hsieh
Jui-Yu
JY
Wu
Yu-Hsuan
YH
Jen
Chih-Hung
CH
Tsuang
Yang-Hwei
YH
Chiou
Shih-Hwa
SH
Partanen
Jukka
J
Anderson
Heidi
H
Jaatinen
Taina
T
Yu
Yau-Hua
YH
Wang
Hsei-Wei
HW
D000071916:AC133 Antigen; D015703:Antigens, CD / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D054337:Cell Dedifferentiation; D002460:Cell Line; D002469:Cell Separation; D065150:Cellular Reprogramming; D002874:Chromosome Mapping; D016000:Cluster Analysis; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D050989:GATA2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006023:Glycoproteins / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010455:Peptides / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*
D000071916:AC133 Antigen; D015703:Antigens, CD; D018952:Antigens, CD34; D050989:GATA2 Transcription Factor; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides