TWIST family of basic helix-loop-helix transcription factors mediate human mesenchymal stem cell growth and commitment.
The TWIST family of basic helix-loop-helix transcription factors, Twist-1 and Dermo-1 are known mediators of mesodermal tissue development and contribute to correct patterning of the skeleton. In this study, we demonstrate that freshly purified human bone marrow-derived mesenchymal stromal/stem cells (MSC) express high levels of Twist-1 and Dermo-1 which are downregulated following ex vivo expansion. Enforced expression of Twist-1 or Dermo-1 in human MSC cultures increased expression of the MSC marker, STRO-1, and the early osteogenic transcription factors, Runx2 and Msx2. Conversely, overexpression of Twist-1 and Dermo-1 was associated with a decrease in the gene expression of osteoblast-associated markers, bone morphogenic protein-2, bone sialoprotein, osteopontin, alkaline phosphatase and osteocalcin. High expressing Twist-1 or Dermo-1 MSC lines exhibited an enhanced proliferative potential of approximately 2.5-fold compared with control MSC populations that were associated with elevated levels of Id-1 and Id-2 gene expression. Functional studies demonstrated that high expressing Twist-1 and Dermo-1 MSC displayed a decreased capacity for osteo/chondrogenic differentiation and an enhanced capacity to undergo adipogenesis. These findings implicate the TWIST gene family members as potential mediators of MSC self-renewal and lineage commitment in postnatal skeletal tissues by exerting their effects on genes involved in the early stages of bone development.
Isenmann
Sandra
S
Mesenchymal Stem Cell Group, Division of Haematology, Institute of Medical and Veterinary Science/Hanson Institute/ CSCR, University of Adelaide, SA, Australia.
Arthur
Agnieszka
A
Zannettino
Andrew C W
AC
Turner
Jenna L
JL
Shi
Songtao
S
Glackin
Carlotta A
CA
Gronthos
Stan
S
D050156:Adipogenesis / Q000502:physiology; D000328:Adult; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001846:Bone Development / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation / Q000502:physiology; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000378:metabolism; D010012:Osteogenesis / Q000502:physiology; D011506:Proteins / Q000032:analysis / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000032:analysis / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
D015415:Biomarkers; D009687:Nuclear Proteins; D011506:Proteins; D012097:Repressor Proteins; C103173:TWIST1 protein, human; C486274:TWIST2 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; C096852:Twist2 protein, mouse