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 Associate Scientist in the Division of Reproductive & Developmental Sciences of ONPRC, Oregon Stem Cell Center and Departments of Obstetrics & Gynecology and Molecular & Medical Genetics, and co-director of the ART/ESC core at the Center. 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.
Tachibana M, Sparman M, Ramsey C, Ma H, Lee HS, Penedo MC, Mitalipov S. Generation of chimeric rhesus monkeys. Cell. 2012 Jan 20;148(1-2):285-95.
Sparman ML, Tachibana M, Mitalipov SM. Cloning of non-human primates: the road "less traveled by. Int J Dev Biol. 2010;54(11-12):1671-8
Tachibana M, Sparman M, Mitalipov S. Chromosome transfer in mature oocytes. Nat Protoc. 2010;5(6):1138-47
Sritanaudomchai H, Ma H, Clepper L, Gokhale S, Bogan R, Hennebold J, Wolf D, Mitalipov S. Discovery of a novel imprinted gene by transcriptional analysis of parthenogenetic embryonic stem cells. Hum Reprod. 2010 Aug;25(8):1927-41
Blin G, Nury D, Stefanovic S, Neri T, Guillevic O, Brinon B, Bellamy V, Rücker-Martin C, Barbry P, Bel A, Bruneval P, Cowan C, Pouly J, Mitalipov S, Gouadon E, Binder P, Hagège A, Desnos M, Renaud JF, Menasché P, Pucéat M. A purified population of multipotent cardiovascular progenitors derived from primate pluripotent stem cells engrafts in postmyocardial infarcted nonhuman primates. J Clin Invest. 2010 Apr 1;120(4):1125-39.
Cohen NM, Dighe V, Landan G, Reynisdóttir S, Palsson A, Mitalipov S, Tanay A.DNA methylation programming and reprogramming in primate embryonic stem cells. Genome Res. 2009 Dec;19(12):2193-201.
Sritanaudomchai H, Sparman M, Tachibana M, Clepper L, Woodward J, Gokhale S, Wolf D, Hennebold J, Hurlbut W, Grompe M, Mitalipov S.CDX2 in the formation of the trophectoderm lineage in primate embryos. Dev Biol. 2009 Nov 1;335(1):179-87.
Tachibana M, Sparman M, Sritanaudomchai H, Ma H, Clepper L, Woodward J, Li Y, Ramsey C, Kolotushkina O, Mitalipov S. Mitochondrial gene replacement in primate offspring and embryonic stem cells. Nature. 2009 Sep 17;461(7262):367-72.
Sparman M, Dighe V, Sritanaudomchai H, Ma H, Ramsey C, Pedersen D, Clepper L, Nighot P, Wolf D, Hennebold J, Mitalipov S. Epigenetic reprogramming by somatic cell nuclear transfer in primates. Stem Cells. 2009 Jun;27(6):1255-64.
Dighe V, Clepper L, Pedersen D, Byrne J, Ferguson B, Gokhale S, Penedo MC, Wolf D, Mitalipov S. Heterozygous embryonic stem cell lines derived from nonhuman primate parthenotes. Stem Cells. 2008 Mar;26(3):756-66.
Byrne JA, Pedersen DA, Clepper LL, Nelson M, Sanger WG, Gokhale S, Wolf DP, Mitalipov SM. Producing primate embryonic stem cells by somatic cell nuclear transfer. Nature. 2007 Nov 22;450(7169):497-502.
See a full listing of Dr. Mitalipov's publications