Professor - Pathology and Laboratory Medicine
Phone: (608) 263-0058
RESEARCH INTERESTS - Hematopoietic development from pluripotent stem cells; de novo generation of hematopoietic stem cells, modeling leukemia stem cells using reprogramming technologies.
MD, Kiev Medical Institute, Kiev, Ukraine
PhD, Kiev Institute of Pediatrics, Obstetrics, and Gynecology
Hematopoietic stem cell transplantation has become the standard of care for treatment of many otherwise incurable diseases such as leukemia, lymphoma and multiple myeloma. In addition, hematopoietic stem cell transplantation is used for treatment of hereditary disorders such as anemia (sickle-cell anemia, beta-thalassemia, and aplastic anemia), inborn errors of metabolism, immunodeficiencies, and autoimmune diseases. However, insufficient numbers of hematopoietic stem cells, graft failure, inadequate anti-tumor immune response after transplantation, and graft-versus- host disease remain significant limitations to the success of hematopoietic stem cell transplantation. The main focus of research in my lab is to significantly advance the clinical use of stem cells through development of novel sources of hematopoietic stem cells and mature blood cells for transplantation, transfusion and cancer immunotherapy. We focused on the following strategies to generate alternative sources of therapeutic blood cells:
- Directed differentiation of human embryonic stem (hES) cells and inducedpluripotent stem (iPS) cells into the hematopoietic stem and mature blood cells.
- Reprogramming of pluripotent stem cells and non-hematopoietic somatic cells into the blood cells.
Using these methodologies, we anticipate generating immunologically compatible hematopoietic stem and immunotherapeutic cells in large quantities. In this way we can eliminate serious complications of bone marrow transplantation such as graft-versus-host disease and transplant failure, and at the same time generate a significant anti-tumor immune response.
We use integrative approaches, including genomics, proteomics and bioinformatics, to achieve the outlined goals and to understand important cellular, and molecular events leading to blood cell development and diversification. We already developed a very efficient system for hematopoietic and endothelial differentiation of hES and iPS cells, and directed differentiation of hES cells toward red blood cells, dendritic cells, macrophages, osteoclasts, and granulocytes. In addition, we defined the major cellular pathways leading to formation of blood cells and identified several novel hematoendothelial, hematopoietic and mesenchymal progenitors. Through comparative analysis of transcriptome and engraftment properties of these novel progenitors and fetal primitive blood cells as well as employing loss-of- and gain-on-function and lienage-tracing experiments, we expect to gain fundamental insights into molecular mechanisms leading to blood cell development. These studies could ultimately revolutionize cellular therapies for blood cancer and hereditary blood disease, and can be exploited for discovery of new drugs regulating hematopoietic stem cells, as well.
- Uenishi G, Jung HS, Kumar A, Park MA, Hadland BK, McLeod E, Raymond M, Moskvin O, Zimmerman CE, Theisen DJ, Swanson S, Tamplin O, Zon LI, Thomson JA, Bernstein ID and Slukvin II. NOTCH Signaling Specifies Arterial-Type Definitive Hemogenic Endothelium from Human Pluripotent Stem Cells. Nature Communications 2018 May 8;9(1):1828.
- Kumar A, D’Souza SS, Moskvin OV, Toh H, Wang B, Zhang J, Swanson S, Guo LW, Thomson JA, Slukvin II. Specification and Diversification of Pericytes and Smooth Muscle Cells from Mesenchymoangioblasts. Cell Rep. 2017 May 30;19(9):1902-1916.
- Park MA, Kumar A, Jung HS, Uenishi G, Moskvin OV, Thomson JA, and Slukvin II. Activation of Arterial Program Drives Development of Definitive Hemogenic Endothelium with Lymphoid Potential. Cell Reports 2018 May 22, 23: 2467–2481.
- Kumar A, Lee JH, Suknuntha K, D’Souza SS, Thakur AS, Slukvin II. NOTCH Activation at the Hematovascular Mesoderm Stage Facilitates Efficient Generation of T Cells with High Proliferation Potential from Human Pluripotent Stem Cells. J Immunol. 2019 Feb 1;202(3):770-776. doi: 10.4049/jimmunol.1801027. Epub 2018 Dec 21.
- Brok-Volchanskaya V.S., Bennin D. A., Suknuntha K, Klemm L. C., Huttenlocher A., Slukvin I. Effective and rapid generation of functional neutrophils from induced pluripotent stem cells using ETV2 modified mRNA. Stem Cell Reports. 2019 Dec 10;13(6):1099-1110.
- Choi K., Vodyanik M, Togarrati P, Suknuntha K, Kumar A, Samarjeet F, Probasco M, Tian S, Stewart R, Thomson J, and Slukvin I. Identification of the hemogenic endothelial progenitor and its direct precursor in human pluripotent stem cell cultures. Cell Rep. 2012 Sep 27;2(3):553-67.
- Hu K, Yu J, Suknuntha K, Tian S, Montgomery K, Choi KD, Stewart R, Thomson JA, Slukvin II. Efficient generation of transgene-free induced pluripotent stem cells from normal and neoplastic bone marrow and cord blood mononuclear cells. Blood. 2011 117(14):e109-119.
- Vodyanik MA, Yu J, Zhang X, Tian S, Stewart R, Thomson JA, Slukvin II. A mesoderm-derived precursor for mesenchymal stem and endothelial cells. Cell Stem Cell 2010 Dec 3;7(6):718-29
- Choi KD, Vodyanik MA, Slukvin II. Generation of mature human myelomonocytic cells through expansion and differentiation of pluripotent stem cell–derived lin-CD34+CD43+CD45+ progenitors. Journal of Clinical Investigation. 2009;119(9):2818-29.
- Yu J, Hu K, Smuga-Otto K, Tian S, Stewart R, Slukvin II, Thomson JA. Human Induced Pluripotent Stem Cells Free of Vector and Transgene Sequences. Science. 2009. May 8;324(5928):797-801.
- Choi K., Yu J, Smuga-Otto K, Salvagiotto G, Rehrauer W, Vodyanik M, Thomson J, and Slukvin I. Hematopoietic and endothelial differentiation of human induced pluripotent stem cells. Stem Cells. 2009; 27(3):559-567.
- Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007; 318(5858): 1917-20.
- Slukvin I. Hematopoietic specification from human pluripotent stem cells: current advances and challenges toward de novo generation of hematopoietic stem cells. Blood. 2013 Dec 12;122(25):4035-46.
- Elcheva I, Brok-Volchanskaya V, Kumar A, Liu P, Lee J, Tong L, Vodyanik M, Swanson S, Stewart R, Kyba M, Yakubov E, Cooke J, Thomson JA, and Slukvin I. Direct Induction of Hematoendothelial Program in Human Pluripotent Stem Cells by Transcriptional Regulators. Nature Communications in press.