Shoukhrat M. Mitalipov

Pluripotent embryonic stem (ES) cells are important as a unique research tool that allows investigation of the mechanisms regulating early primate development and differentiation in vitro. Human ES 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 derivation, maintenance and directed differentiation of primate ES 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 epigenetic mechanisms of oocyte-induced reprogramming after somatic cell nuclear transfer (SCNT). The objective is to develop efficient protocols for deriving patient-matched pluripotent stem cells via SCNT into oocytes or direct reprogramming using natural epigenetic mechanisms. Another goal is production of knock-out rhesus monkeys using SCNT. 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 SCNT and parthenogenetic monkey ES cells suitable for autologous transplantation into existing monkeys.

The Mitalipov lab is also investigating novel gene therapy approaches for the treatment of human diseases. Mutations in mitochondrial (mt)DNA 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.

Biography

Shoukhrat Mitalipov is an Associate Scientist in the Division of Reproductive Sciences, a Research Associate Professor at the 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, Russian Academy of Medical Sciences. 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.

Key Publications

Masahito Tachibana, Michelle Sparman, Hathaitip Sritanaudomchai, Hong Ma, Lisa Clepper, Joy Woodward, Ying Li, Cathy Ramsey, Olena Kolotushkina & Shoukhrat Mitalipov. Mitochondrial Gene Replacement in Primate Offspring and Embryonic Stem Cells.Advance online publication 26 August 2009. doi:10.1038/nature08368.

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. PMID: 19489081

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. PMID: 18192229

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. PMID: 18004281

Mitalipov SM, Zhou Q, Byrne JA, Ji WZ, Norgren RB, Wolf DP. Reprogramming following somatic cell nuclear transfer in primates is dependent upon nuclear remodeling. Hum Reprod. 2007 Aug;22(8):2232-42. PMID: 17562675

Mitalipov S, Kuo HC, Byrne J, Clepper L, Meisner L, Johnson J, Zeier R, Wolf D. Isolation and characterization of novel rhesus monkey embryonic stem cell lines. Stem Cells. 2006 Oct;24(10):2177-86. PMID: 16741224

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