Submitted on October 26, 2005
Accepted on March 13, 2006
Transplanted Embryonic Stem Cells Successfully Survive, Proliferate and Migrate to Damaged Regions of the Mouse Brain
Anand S. Srivastava 1,
Steve Shenouda 1,
Rangnath Mishra 2,
Ewa Carrier 2*
1 Moores UCSD Cancer Center, Department of Medicine, University of California San Diego, San Diego, California
2 Division of Nephrology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio
* To whom correspondence should be addressed. E-mail: assrivastava{at}ucsd.edu.
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Abstract |
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An understanding of feasibility of implanting embryonic (ES) cells, their behavior of migration in response to lesions induced in brain tissues and mechanism of their in vivo differentiation into neighboring neural cells is essential for developing and refining ES cell transplantation strategies for the repairing damages in nervous system, as well as for understanding the molecular mechanism underlying neurogenesis. We hypothesized that damaged neural tissues offer a niche where injected ES cells can migrate and differentiate into the neural cells. We inflicted damage in murine (C57BL/6) brain by injecting PBS into the left frontal and right caudal regions and confirmed neural damage by histochemistry. Enhanced yellow fluorescent protein (EYFP) expressing embryonic stem cells were injected into the non-damaged left caudal portion of the brain. Using immunohistochemistry and fluorescent microscopy, we observed migration of ES cells from the injection site (left caudal) to the damaged site (right caudal and left frontal).
Survival of the injected ES cells was confirmed by the real-time PCR analysis of stemness genes such as OCT4, SOX2 and FGF4. The portions of the damaged neural tissues containing ES cells demonstrated a four-fold increase in expression of these genes after one week of injection in comparison to non-injected ES cell murine brain suggesting proliferation. An increased level of PDGFr demonstrated that ES cells responded to damaged neural tissues, migrated to the damaged site of the brain and proliferated. These results demonstrate that undifferentiated ES cells migrate to the damaged regions of brain tissue, engraft and proliferate. Thus, damaged brain tissue provides a niche that attracts ES cells to migrate and proliferate.
