Stem Cell Biology
Although there have been advances in the understanding of how stem cells proliferate and differentiate, we do not fully understand the mechanisms that control the bone marrow stem cell compartment. One of the major challenges has been to understand the role of the "bone marrow microenvironment" in the regulation of the proliferation and differentiation of hematopoietic stem cells (HSC). Although poorly characterized, this microenvironment is composed of stromal cells, including myofibroblasts, adipocytes, and osteoblasts, that originate from mesenchymal progenitors -- MSCs-, hematopoietic-derived cells such as lymphocytes and macrophages, and of extracellular matrix proteins (collagen, fibronectin, vitronectin, laminin, hemonectin, among others). The stroma provides growth factors, chemoattractants, anchorage, and scaffolding for the correct development of hematopoiesis.
Basic research studies are carried out in Dr. Cancelas' laboratories in Hoxworth and in the Research Building of the Cincinnati Children's Hospital Medical Center. These studies utilize state-of-the-art molecular methods and rely heavily on gene-targeted and transgenic mice. These methods include genotyping, flow-cytometry, immunofluorescence analysis, reverse transcription (RT)-PCR, cell culture and cell signaling analysis, and retroviral vector construction and retrovirus-mediated transduction. New knowledge gained from these studies have important implications for understanding pathological conditions associated with genetic diseases and for designing improved methods to grow and expand these cells in the laboratory.
Molecular Mechanisms Controlling HSC Engraftment and Mobilization - Selected Publications:
1. Klf5 controls bone marrow homing of stem cells and progenitors through Rab5-mediated membrane Î²1/Î²2-integrin expression. Taniguchi Ishikawa E, Chang KH, Nayak R, Olsson HA, Ficker AM, Dunn SK, Madhu MN, Sengupta A, Whitsett JA, Grimes HL, Cancelas JA. Nat Commun 2013 Apr 3;4:art. No. 1660. doi: 10.1038/ncomms2645.
2. Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells. Taniguchi Ishikawa E, Gonzalez-Nieto D, Ghiaur G, Dunn SK, Ficker AM, Murali B, Madhu M, Gutstein DE, Fishman GI, Barrio LC, Cancelas JA. Proc Natl Acad Sci USA 2012 Jun 5;109(23):9071-6. Epub May 18. PMID 22611193 PMC 3384185
3. Connexin-43 in the osteogenic BM niche regulates its cellular composition and the bidirectional traffic of hematopoietic stem cells and progenitors. Gonzalez-Nieto D, Li L, Köhler A, Ghiaur G, Ishikawa E, Sengupta A, Madhu M, Arnett J, Santho RA, Dunn S, Fishman G, Gutstein D, Civitelli R, Barrio L, Gunzer M, Cancelas J. Blood 2012 May 31;119(22):5144-54.
Extrinsic and Small GTPase Signaling in Cancer Stem Cells and Progenitors - Selected Publications:
1. Rho GTPases control specific cytoskeleton dependent functions of hematopoietic stem cells. [Review] Nayak RC, Chang K-H, Vaitinadin N-S, Cancelas JA. Immunol Rev 2013 Nov;256(1):255-268.
2. Vav3 collaborates with p190-BCR-ABL in lymphoid progenitor leukemogenesis, proliferation and survival. Chang KH, Sanchez-Aguilera A, Shen S, Sengupta A, Madhu MN, Ficker AM, Dunn SK, Kuenzi AM, Anrett JL, Santho RA, Agirre X, Perentesis JP, Deininger MW, Zheng Y, Bustelo XR, Williams DA, Cancelas JA. Blood 2012 Jul 26;120(4):800-11.
For additional information:
Cancelas Laboratory. Division of Experimental Hematology and Cancer Biology Cincinnati Children's Hospital Medical Center