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Stem Cells and Regenerative Medicine

Nonhuman primate stem cells differentiating into neurons.
Figure 1. Nonhuman primate stem cells differentiating into neurons. Image courtesy of Dr. Marina Emborg, Wisconsin National Primate Research Center.

Regenerative medicine is the process of creating living, functional tissues to repair or replace tissue or organ function lost due to damage or congenital defects. Regenerative medicine has the potential to solve the problem of the shortage of organs available for donation. It also holds the promise of repairing or replacing damaged tissues and organs in the body by stimulating organs previously considered irreparable to heal themselves. The recent discovery of the reprogramming of adult cells to a pluripotent state provides opportunities to address a major problem of regenerative medicine: immune rejection of transplanted tissue. The ability to generate differentiated cells and tissues using cells from specific patients will facilitate individualized medicine and eventually lead to specialized therapies. The field is moving toward translation to clinical practice and is becoming increasingly dependent on animal models and information regarding the potential therapeutic efficacy of new technologies. Generating the correct type and quantity of the specific cell types required for replacement therapy is a significant challenge, as are the problems associated with introducing these cells into the proper environment in vivo and overcoming immune reactions. Finding solutions to these problems will require extensive testing in experimental animal models.

Along with rodents, several other animal species are being developed as models for various studies in the field of regenerative medicine. Understanding the properties and capabilities of stem cells derived from such animals as fish, rabbits, dogs, pigs, sheep, goats, and monkeys will increase the potential for the use of the most appropriate systems for modeling particular human disease conditions or for other medical applications. Non-rodent species, especially “large animal models,” provide important advantages for transplantation studies, including large size, similarity to human physiology and pathology, and longer life span, thus facilitating translation to studies in humans. The use of animal stem cells as a model for human cells in procedures related to regenerative medicine requires in-depth understanding of common regulatory pathways, as well as species-specific properties and their impact on potential therapeutic applications.

Stem cells.
Figure 2. Hematopoietic stem cells from a nonhuman primate. Image courtesy of Dr. Igor Slukvin, Wisconsin National Primate Research Center.

As part of the effort to respond to the needs and challenges identified by the research community and outlined in the report for the 2012 workshop “Improving Animal Models for Regenerative Medicine” organized by ORIP and representatives from several other NIH Institutes, ORIP published several funding opportunity announcements, including PAR-19-176, titled “Methods Development for Cryogenic or Other Long-term Preservation and Revival of Drosophila and Zebrafish Genetic Stocks (R21 Clinical Trial Not Allowed).” The intent of this initiative is to facilitate the use of stem cell–based therapies for regenerative medicine. The initiative focuses on the following areas: (1) comparative analysis of animal and human stem cells to provide information for selection of the most predictive and informative model systems, (2) development of new technologies for stem cell characterization and transplantation, and (3) improvement of animal disease models for stem cell–based therapeutic applications.

Examples of projects funded by ORIP:

Immune Compromised Zebrafish for Cell Transplantation
David Michael Langenau
Massachusetts General Hospital
Boston, MA

Immunogenicity of Human Stem Cell–Derived Beta Cells and Muscle Cells in Humanized Mice
Dale Leslie Greiner
University of Massachusetts
Worcester, MA

Transplantation of Testis Stem Cells in Large Animals
Ina Dobrinski
University of Calgary
Calgary, Canada

Derivation of Functional Spermatogonia Stem Cells from Rhesus Macaque iPSCs
Charles Easley
University of Georgia
Athens, GA

Comparison of human and mouse stem cells: differences in microRNA regulation
Rui Zhao
University of Alabama at Birmingham
Birmingham, AL

Derivation of chimera competent pig embryonic stem cells under a novel condition
Jun Wu
UT Southwestern Medical Center
Dallas, TX

Genetically Diverse Mouse Embryonic Stem Cells: A Platform for Cellular Systems Genetics
Laura Reinholdt
The Jackson Laboratory
Bar Harbor, ME