The Slukvin Laboratory
Faculty > Igor I. Slukvin
Igor I. Slukvin
Assistant Professor, Pathology and Laboratory Medicine
islukvin@wisc.edu
Organ System/Disease Focus
Blood disease
Aligned Research Focus
Hematopoietic differentiation of human pluripotent stem cells, hematopoietic stem cell (HSC) biology
Research Description
Pluripotent stem cells, including embryonic stem (ES) and induced pluripotent stem (iPS) cells, represent a unique population of cells capable of self-renewal and differentiation. Pluripotent stem cells form any cell type in the body and can serve as a scalable cell source for transplantation and tissue engineering.
The main focus of my research is to establish the differentiation of human pluripotent stem cells into the hematopoietic progenitors and mature blood cells in order to understand molecular mechanisms of early hematopoietic differentiation and to provide a novel source of cells for bone marrow transplantation, transfusion and cancer immunotherapy.
We demonstrated that when undifferentiated human ES cells are transferred to a coculture system containing mouse OP9 feeders, the cells undergo a series of changes leading to the formation of a full spectrum of myeloid progenitors, all of which express CD43. The first of these cells also express glycophorin A (CD235a) and CD41a (a marker of megakaryocytes) and appear restricted to the erythro-megakaryocytic lineages. Cells with a broader lympho-myeloid differentiation repertoire and a lin-CD34+CD43+CD45- phenotype appear next. Finally, a lin-CD34+CD43+CD45+ population emerges. These latter cells are highly enriched in myeloid progenitors but also show some lymphoid differentiation potential.
Analysis of SAGE libraries established from ES cell-derived hematopoietic progenitors and fetal liver hematopoietic cells revealed a strong similarity between the most primitive human ES cell-derived hematopoietic cells and the fetal liver HSCs, with differences mainly affecting genes that regulate HSC development, self-renewal and homing, chromatin remodeling, AP1 transcription complex genes, and non-coding RNAs. These findings set the stage for future experiments directed at the identification of genes essential for establishing multipotent hematopoietic cells with long-term engraftment potential and obtaining hES cell-derived cells with transplantable in vivo repopulating activity.
We also demonstrated that iPS cell lines are capable of differentiation into blood and endothelial cells with a differentiation pattern very similar to that observed with hES cells. These findings provide strong evidence that iPS cells are very similar to ES cells, and differentiation systems established for ES cells can be readily applied to iPS cells.
Currently our laboratory is working on 1) identification of genes essential for acquisition of long-term engraftment potential by pluripotent stem cell-derived primitive hematopoietic cells; 2) defining upstream progenitors of primitive hematopoietic cells and downstream lineage-restricted hematopoietic progenitors from pluripotent stem cells; 3) establishing non-human primate model of ES cells and iPS cell-based cellular therapy for blood and immune system disorders.
Selected References
Choi K, Yu J, Smuga-Otto K, Salvagiotto G, Rehrauer W, Vodyanik M, Thomson J, Slukvin I. Hematopoietic and endothelial differentiation of human induced pluripotent stem cells. Stem Cells. In press(2008).
Salvagiotto G., Zhao Y, Vodyanik M, Ruotti V, Stewart R, Marra M, Thomson J, Eaves C, Slukvin I. Molecular Profiling Reveals Similarities and Differences Between Primitive Subsets of Hematopoietic Cells Generated In Vitro from Human Embryonic Stem Cells and In Vivo during Embryogenesis. Experimental Hematology 2008 36(10):1377-89.
Vodyanik MA, Thomson JA, Slukvin II. Leukosialin (CD43) defines hematopoietic progenitors in human embryonic stem cell differentiation cultures. Blood 108(6):2095-2105. 2006.
Slukvin II, Vodyanik MA, Thomson JA, Gumenyuk ME, Choi K. Directed differentiation of functional dendritic cells form human embryonic stem cells through the myeloid pathway. Journal of Immunology 176:2924-2932. 2006.
Yu J, Vodyanik MA, He P, Slukvin II, Thomson JA. Human Embryonic Stem Cells Reprogram Myeloid Precursors Following Cell-Cell Fusion. Stem Cells. 24(1):168-176. 2006.