Stem Cell Biology at Penn Vet
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.
Dr. Ina Dobrinski’s research investigats male germline stem cell biology in mice and large domestic animal models. Application of germ cell transplantation to large domestic animals now allows the study the stem cell niche in non-rodent mammalian species. Manipulation of the male germ line and transplantation of germline stem cells is a novel, more efficient way of generating transgenic non-rodent animals for the study of human and animal disease in non-rodent models as well as for the use of transgenic animals in the biotechnology industry and potentially agricultural production. Recently, proof-of-principle was achieved that genetic alteration of male germ line stem cells followed by germ cell transplantation results in germ line transgenesis in a domestic animal model.
Work in Dr. Jeremy Wang’s laboratory focuses on studying the development of mouse spermatogonia and meiosis using genetic, cell biological and biochemical approaches. Proliferation and differentiation of spermatogonia are studied by generating mutant mice and identifying markers for differentiation. Another major focus is on regulation of spermatogonial development by Sertoli cells (the niche cells). A Sertoli cell-specific gene is currently being chcracterized that might hold the key for the temporal regulation of male germ line in mice and humans.
Dr. John McLaughlin’s research explores the potential of pluripotent stem cells derived from uniparental mouse embryos to regenerate complex tissues after transplantation. Recent work demonstrated functional regeneration of hematopoietic tissue and ongoing work explores the potential of uniparental stem cells to contribute to regeneration of neural tissue and liver.
In collaboration with 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. Mike 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.
Drs. Brinster, Dobrinski and McLaughlin are members of the Center for Animal Transgenesis and Germ Cell Research at New Bolton Center. Investigators involved in stem cell research at Penn Vet are also affiliated with the Institute for Regenerative Medicine at the University of Pennsylvania.
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.