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Blood, 1 April 2006, Vol. 107, No. 7, pp. 2968-2975.
Prepublished online as a Blood First Edition Paper on December 6, 2005; DOI 10.1182/blood-2005-05-2138.
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Submitted June 6, 2005
Accepted November 22, 2005
Enhanced engraftment of hematopoietic stem/progenitor cells by the transient inhibition of an adaptor protein, Lnk
Hitoshi Takizawa, Chiyomi Kubo-Akashi, Ikuo Nobuhisa, Sang-Mo Kwon, Masanori Iseki, Tetsuya Taga, Kiyoshi Takatsu, and Satoshi Takaki*
Division of Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
* Corresponding author; email: takakis{at}ims.u-tokyo.ac.jp.
Hematopoietic stem cells (HSCs) are the key elements responsible for maintaining blood cell production throughout life and for lymphohematopoietic reconstitution following bone marrow (BM) transplantation. Enhancement of the engrafting potential and expansion capabilities of HSCs as well as hematopoietic progenitor cells (HPCs), has been a long-time desire, as a means of reducing the risks and difficulties accompanied with BM transplantation. The ability of HSCs/HPCs to reconstitute the hematopoietic system of irradiated hosts is negatively regulated by an intracellular adaptor protein, Lnk. Here, we have identified the functional domains of Lnk, and developed a dominant-negative (DN) Lnk mutant that inhibits the functions of Lnk endogenously expressed in the HSCs/HPCs and, thereby, potentiates the HSCs/HPCs for engraftment. Importantly, even transient expression of DN-Lnk in HSCs/HPCs facilitated their engraftment under nonmyeloablative conditions and fully reconstituted the lymphoid compartments of immunodeficient host animals. HPCs expressing DN-Lnk were efficiently trapped by immobilized vascular cell adhesion molecule-1 (VCAM-1) in a transwell migration assay, suggesting involvement of Lnk in the regulation of cell mobility or cellular interaction in microenvironments. Transient inhibition of Lnk or Lnk-mediated pathways could be a potent approach to augment engraftment of HSCs/HPCs without obvious side effects.
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