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STEM CELL GENETICS AND GENOMICS

Identification and Functional Analysis of Candidate Genes Regulating Mesenchymal Stem Cell Self-Renewal and Multipotency

Cartilage Biology and Orthopaedics Branch, National Institute of Arthritis, and Musculoskeletal and Skin Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA

Key Words. Mesenchymal stem cells • Transdifferentiation • Self-renewal • Microarray

Correspondence: Rocky S. Tuan, Ph.D.,Cartilage Biology and Orthopaedics Branch, National Institute of Arthritis, and Musculoskeletal and Skin Diseases, 50 South Drive, Room 1503, MSC 8022, National Institutes of Health, Bethesda, Maryland 20892-8022, USA. Telephone: 301-451-6854; Fax: 301-435-8017; email: tuanr{at}mail.nih.gov

Received December 1, 2005; accepted for publication March 15, 2006.
First published online in STEM CELLS EXPRESS   March 30, 2006.


Adult human mesenchymal stem cells (hMSCs) possess multilineage differentiation potential, and differentiated hMSCs have recently been shown to have the ability to transdifferentiate into other lineages. However, the molecular signature of hMSCs is not well-known, and the mechanisms regulating their self-renewal, differentiation, and transdifferentiation are not completely understood. In this study, we demonstrate that fully differentiated hMSCs could dedifferentiate, a likely critical step for transdifferentiation. By comparing the global gene expression profiles of undifferentiated, differentiated, and dedifferentiation cells in three mesenchymal lineages (osteogenesis, chondrogenesis, and adipogenesis), we identified a number of "stemness" and "differentiation" genes that might be essential to maintain adult stem cell multipotency as well as to drive lineage-specific commitment. These genes include those that encode cell surface molecules, as well as components of signaling pathways. These genes may be valuable for developing methods to isolate, enrich, and purify homogeneous population of hMSCs and/or maintain and propagate hMSCs as well as guide or regulate their differentiation for gene and cell-based therapy. Using small interfering RNA gene inactivation, we demonstrate that five genes (actin filament-associated protein, frizzled 7, dickkopf 3, protein tyrosine phosphatase receptor F, and RAB3B) promote cell survival without altering cell proliferation, as well as exhibiting different effects on the commitment of hMSCs into multiple mesenchymal lineages.

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