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J. Biol. Chem., Vol. 280, Issue 25, 23691-23697, June 24, 2005

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Neuronal Differentiation of Bone Marrow-derived Stromal Stem Cells Involves Suppression of Discordant Phenotypes through Gene Silencing^*

Hiroshi Egusa, Felix E. Schweizer¶, Chia-Chien Wang||, Yoshizo Matsuka**, and Ichiro Nishimura

From the Division of Advanced Prosthodontics, Biomaterials, and Hospital Dentistry, Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, California 90095, Department of Fixed Prosthodontics, Osaka University Graduate School of Dentistry, Suita City, Osaka 565-0871, Japan, ^¶Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, ^||Department of Biomedical Engineering, UCLA Henry Samueli School of Engineering and Applied Science, Los Angeles, California 90095, and ^**Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, California 90095

Tissue engineering involves the construction of transplantable tissues in which bone marrow aspirates may serve as an accessible source of autogenous multipotential mesenchymal stem cells. Increasing reports indicate that the lineage restriction of adult mesenchymal stem cells may be less established than previously believed, and stem cell-based therapeutics await the establishment of an efficient protocol capable of achieving a prescribed phenotype differentiation. We have investigated how adult mouse bone marrow-derived stromal cells (BMSCs) are guided to neurogenic and osteogenic phenotypes. Naïve BMSCs were found surprisingly active in expression of a wide range of mRNAs and proteins, including those normally reported in terminally differentiated neuronal cells and osteoblasts. The naïve BMSCs were found to exhibit voltage-dependent membrane currents similar to the neuronally guided BMSCs, although with smaller amplitudes. Once BMSCs were exposed to the osteogenic culture condition, the neuronal characteristics quickly disappeared. Our data suggest that the loss of discordant phenotypes during BMSC differentiation cannot be explained by the selection and elimination of unfit cells from the whole BMSC population. The percent ratio of live to dead BMSCs examined did not change during the first 8–10 days in either neurogenic or osteogenic differentiation media, and cell detachment was estimated at <1%. However, during this period, bone-associated extracellular matrix genes were selectively down-regulated in neuronally guided BMSCs. These data indicate that the suppression of discordant phenotypes of differentiating adult stem cells is achieved, at least in part, by silencing of superfluous gene clusters.

Received for publication, December 8, 2004 , and in revised form, March 7, 2005.

^* This work was supported in part by grants-in-aid from the Japan Society for the Promotion of Science and the Ministry of Education, Culture, Sports, Science, and Technology, the Japanese Government (to H. E.), and the dean's pilot research grant from the UCLA School of Dentistry (to I. N.).

To whom correspondence should be addressed: The Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Box 951668, CHS B3-087, Los Angeles, CA 90095. Tel.: 310-794-7612; Fax: 310-825-6345; E-mail: ichiron{at}dent.ucla.edu.

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