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Stem Cell Biology

Penn Vet holds a leadership in the field of stem cell and germ cell biology spearheaded by the pioneering work of Dr. Ralph Brinster.

Currently, Penn vet scientists investigate stem cell models ranging from germline stem cells in the mammalian testis and embryo-derived stem cells from animals and humans to somatic stem cells derived from bone marrow, epithelial cells and adipose tissue.

Research in Dr. Ralph Brinster’s laboratory focuses on the biology of the spermatogonial stem cell (SSC), which is responsible for the continuity of spermatogenesis in the adult male. A spermatogonial transplantation technique has been developed in rodents that provides a functional assay of stem cell activity, thereby enabling for the first time an analysis of this unique and valuable stem cell population.

Development of culture and gene modification methods for rodent SSCs will lay the foundation for similar approaches in larger animals, particularly farm animals. Since the SSC is the only adult stem cell for which there exists a long-term in vitro culture system and a quantitative functional transplantation assay, it provides a powerful model to understand stem cell function in all adult stem cell systems.

Work in Dr. Jeremy Wang’s laboratory focuses on the study of meiosis in mice and humans. Meiosis, a cell division unique to germ cells, allows the reciprocal exchange of genetic material between paternal and maternal genomes. Meiosis generates the genetic diversity necessary for evolution of species. Abnormality in meiosis is a leading cause of birth defects and infertility. His laboratory’s research interests include molecular genetics of chromosomal synapsis, DNA double-strand break repair, homologous recombination, genetic causes of male infertility in humans, and piRNA biogenesis.

Dr. Christopher Lengner’s lab is broadly interested in the mechanisms by which both somatic and embryonic stem cells acquire and maintain developmental potency. His laboratory is also exploring how deregulation of these mechanisms can contribute to oncogenic transformation and tumorigenesis, and how we can learn to manipulate these mechanisms for application in disease modeling and regenerative medicine

Dr. Montserrat Anguera’s lab studies the roles of long non-coding RNAs in epigenetic gene regulation in human and mouse pluripotent stem cells. Human female pluripotent stem cells can vary widely in quality -- more so than male cells or mouse cells of either sex -- and one of her goals is to determine the cause of this epigenetic variability and its relationship to female-specific cancers.

In the laboratory of Dr. Rose Nolen-Walston, the regenerative potential of pulmonary tissue is being studied, particularly function and gene expression of putative pulmonary stem cells (BASCs) in a mouse model for compensatory lung growth.

Dr. Michael Atchison’s laboratory studies the function of the transcription factor, Oct4, to maintain pluripotency of embryonic stem cells. The laboratory showed that post-translational modification of Oct4 plays a significant regulatory role in early embryonic development and disease. Studies exploring how Oct4 binds to specific gene promoters in association with Polycomb group proteins to either activate or repress transcription will likely reveal mechanisms that control early embryonic development, and why Oct4 is necessary for pluripotency. In other studies, the Atchison laboratory is exploring the role of transcription factor, YY1, in hematopoietic stem cell biology. This work may reveal functions of YY1 that could be exploited for either augmentation of bone marrow transplant therapies, or for inhibition of YY1 function in hematopoietic malignancies.

Research in Dr. Narayan Avadahni’s laboratory focuses on mitochondrial function, apoptosis, signal transduction and oncogenesis. 

Drs. Kurt Hankenson and Susan Volk study the regulation of proliferation and differentiation in adult, bone marrow-derived mesenchymal stem cells (MSC). Since MSC are easily purified from marrow and can develop into multiple cell types, they are actively pursued as a cell therapeutic not only for bone but for brain, heart, skin, and cartilage. However, many aspects need to be addressed before efficient therapeutic protocols can be developed. Current work investigates interaction between MSC and their microenvironment considering a variety of local regulatory mechanisms as well as delivery of MSC to injured tissues in hydrogels.

Dr. Makoto Senoo’s research explores the potential of adult stem cells to cross their own lineage and establish a framework of stem cell plasticity using epithelial stem cells as a model. Stem cell aging will also be studied in a cell autonomous manner by comparing stem cells from different lifetime points in the same environmental platform. Factors produced by the stem cell “niche” will also be identified and changes in the expression of these environmental factors during aging are investigated. Insights obtained will lead to a novel approach to utilize adult stem cells in regenerative medicine.

Work in Dr. Dean Richardson's laboratory studies the potential of marrow- and adipose-derived mesenchymal stem cells for the treatment of osteoarthritis and tendon/ligament injury. In collaboration with Dr. Jim Wilson's gene therapy program, we are optimizing strategies for gene transfer to mesenchymal stem cells to enhance their therapeutic value. Targeted genetic modification of autologous stem cells provides a promising platform for the regeneration of diseased musculoskeletal tissues in horses and then potentially in other species.

A thorough understanding of stem cell biology from adult and embryonic sources is essential for the realization of their therapeutic potential. It is expected that novel stem cell based therapies can be applied to animal patients long before they can be used in human patients, and without the ethical debate surrounding the use of human stem cells. An advantage of Penn Vet is access to animal models of naturally occurring diseases that are targets for stem cell therapies.