Totipotent and pluripotent stem cells are important as a unique research tool that allows investigation of the mechanisms regulating early primate development and differentiation. Human stem cells also provide the far-reaching foundation for the field of regenerative medicine and offer hope for the treatment of a wide range of clinical conditions that can be attributed to the loss or malfunction of specific cell types. Translational research in the clinically relevant nonhuman primate model is highly desirable to evaluate the safety, feasibility and efficacy of cell-based therapies. The basic research conducted in the lab provides new insights into the generation, maintenance and developmental potential of primate totipotent and pluripotent stem cells.
The overall research goal of Dr. Mitalipov's lab is to use molecular and cellular approaches to answer scientifically and clinically pertinent questions regarding gamete, embryo and stem cell biology. The main focus of ongoing and future studies is to understand the genetic and epigenetic mechanisms responsible for reprogramming of somatic cells to the totipotent and/or pluripotent state using somatic cell nuclear transfer (SCNT) and iPS cell technologies. Specifically, we are interested in the role of mitochondria and mitochondrial (mt)DNA in reprogramming and re-setting the developmental program in experimental totipotent and pluripotent cells derived from aged somatic cells. The objective is to develop efficient protocols for deriving patient-matched "naïve" pluripotent cells via SCNT into oocytes or direct reprogramming.
Another goal is production of genetically modified (knock-out) rhesus monkeys using SCNT or other approaches. Such animals should provide a resource for the study of human diseases and serve as pre-clinical models for new experimental treatments including gene and stem cell based therapies. Several other projects in the lab are focused on the assessment of the safety and efficacy of stem cell based therapies by transplantation studies in a clinically relevant nonhuman primate model. The overall goal of these studies is to take advantage of recent developments in Dr. Mitalipov lab that allowed for the first time derivation of immuno-matched pluripotent cells by SCNT or iPS approaches, suitable for autologous transplantation into adult monkeys.
The Mitalipov lab is also investigating novel gene therapy approaches for the treatment of human diseases. Mutations in mtDNA contribute to a diverse range of still incurable human diseases and disorders including neurodegenerative diseases, myopathies, diabetes, cancer and infertility. MtDNA is maternally inherited through the egg's cytoplasm and it is estimated that at least 1 in 200 born children have an mtDNA mutation that may lead to disease. Mitalipov's team recently demonstrated that the mitochondrial genome can be efficiently replaced in mature nonhuman primate oocytes by spindle-chromosomal complex transfer from one egg to an enucleated, mitochondrial-replete egg. The reconstructed oocytes with the mitochondrial replacement were capable of supporting normal fertilization, embryo development and produced healthy offspring. This discovery suggest that the nuclear genetic material from a patient's egg containing mtDNA mutations could be removed, and transplanted into an enucleated egg containing normal mtDNA donated by a healthy female. A child born following fertilization with the husband's sperm would be free of risk from maternal mtDNA mutations as well as the authentic biological child of the patients. The overall goal of ongoing research initiative in Mitalipov lab is to replicate monkey studies with human oocytes donated by patients carrying mtDNA mutations after informed consent. Healthy egg donors that commit to donating their oocytes for research will be used as mtDNA donors.
For more information visit Mitalipov Lab webpage.
Shoukhrat Mitalipov is an Senior Scientist in the Division of Reproductive & Developmental Sciences of ONPRC, Oregon Stem Cell Center and Departments of Obstetrics & Gynecology and Molecular & Medical Genetics. He earned his Ph.D. degree in Developmental & Stem Cell Biology at the Research Center for Medical Genetics in Moscow, Russia. He came to Utah State University in 1995 to conduct his postdoctoral research in stem cell and developmental biology. Dr. Mitalipov moved to the center in 1998.
Polejaeva I, and Mitalipov S. (2013). Stem cell potency and the ability to contribute to chimeric organisms. Reproduction. 145:R81-88. PMID: 23221011
Tachibana M, Amato P, Sparman M, Gutierrez NM, Tippner-Hedges R, Ma H, Kang E, Fulati A, Lee HS, Sritanaudomchai H, Masterson K, Larson J, Eaton D, Sadler-Fredd K, Battaglia D, Lee D, Wu D, Jensen J, Patton P, Gokhale S, Stouffer RL, Wolf D, and Mitalipov S. (2013). Human Embryonic Stem Cells Derived by Somatic Cell Nuclear Transfer. Cell. 153:1228-38. PMC3772789
Hermann BP, Sukhwani M, Winkler F, Pascarella JN, Peters KA, Sheng Y, Valli H, Rodriguez M, Ezzelarab M, Dargo G, Peterson K, Masterson K, Ramsey C, Ward T, Lienesch M, Volk A, Cooper DK, Thomson AW, Kiss JE, Penedo MC, Schatten GP, Mitalipov S, Orwig KE. Spermatogonial stem cell transplantation into rhesus testes regenerates spermatogenesis producing functional sperm. Cell Stem Cell. 11:715-26. PMC3580057
Lee, HS, Ma, H, Juanes, RC, Tachibana, M, Sparman, M, Woodward, J, Ramsey, C, Xu, J, Kang, EJ, Amato, P, Mair, G, Steinborn, R, Mitalipov, S. (2012). Rapid mitochondrial DNA segregation in primate preimplantation embryos precedes somatic and germline bottleneck. Cell Rep. 1:506-15. PMC3372871
Tachibana M, Amato P, Sparman M, Woodward J, Melguizo Sanchis D, Ma H, Marti Gutierrez N, Tippner-Hedges R, Kang E, Lee H-S, Ramsey C, Masterson K, Battaglia D, Lee D, Wu D, Jensen J, Patton P, Gokhale S, Stouffer R, Mitalipov S. (2012). Towards germline gene therapy of inherited mitochondrial diseases. Nature. Epub. PMC3561483
Tachibana M, Ma H, Sparman ML, Lee HS, Ramsey CM, Woodward JS, Sritanaudomchai H, Masterson KR, Wolff EE, Jia Y, Mitalipov SM. (2012). X-chromosome inactivation in monkey embryos and pluripotent stem cells. Dev Biol. 371:146-155. Epub. 2012. PMC3466365
See a full listing of Dr. Mitalipov's publications