Yan Li1, Wen Xing1, Yong-Zheng He1, Shi Chen1, Steven D Rhodes1, Jin Yuan1, Yuan Zhou1, Jun Shi1, Jie Bai1, Feng-Kui Zhang1, Wei-Ping Yuan1, Tao Cheng1, Ming-Jiang Xu1, Feng-Chun Yang1. 1. 1 Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA ; 2 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China ; 3 Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Abstract
BACKGROUND: Fanconi anemia (FA) is a heterogeneous genetic disorder characterized by a progressive bone marrow aplasia, chromosomal instability, and acquisition of malignancies. Successful hematopoietic cell transplantation (HCT) for FA patients is challenging due to hypersensitivity to DNA alkylating agents and irradiation of FA patients. Early mobilization of autologous stem cells from the bone marrow has been thought to be ideal prior to the onset of bone marrow failure, which often occurs during childhood. However, the markedly decreased response of FA hematopoietic stem cells to granulocyte colony-stimulating factor (G-CSF) is circumventive of this autologous HCT approach. To-date, the mechanism for defective stem cell mobilization in G-CSF treated FA patients remains unclear. METHODS: Fancg heterozygous (Fancg (+/-)) mice utilized in these studies. Student's t-test and one-way ANOVA were used to evaluate statistical differences between WT and Fancg (-/-) cells. Statistical significance was defined as P values less than 0.05. RESULTS: Fancg deficient (Fancg (-/-)) mesenchymal stem/progenitor cells (MSPCs) produce significant lower levels of KC, an interleukin-8 (IL-8) related chemoattractant protein in rodents, as compared to wild type cells. Combinatorial administration of KC and G-CSF significantly increased the mobilization of hematopoietic stem/progenitor cells (HSPCs) in Fancg (-/-) mice. CONCLUSIONS: In summary, our results suggest that KC/IL-8 could be proved useful in the synergistic mobilization of FA HSPCs in combination with G-CSF.
BACKGROUND:Fanconi anemia (FA) is a heterogeneous genetic disorder characterized by a progressive bone marrow aplasia, chromosomal instability, and acquisition of malignancies. Successful hematopoietic cell transplantation (HCT) for FA patients is challenging due to hypersensitivity to DNA alkylating agents and irradiation of FA patients. Early mobilization of autologous stem cells from the bone marrow has been thought to be ideal prior to the onset of bone marrow failure, which often occurs during childhood. However, the markedly decreased response of FA hematopoietic stem cells to granulocyte colony-stimulating factor (G-CSF) is circumventive of this autologous HCT approach. To-date, the mechanism for defective stem cell mobilization in G-CSF treated FA patients remains unclear. METHODS:Fancg heterozygous (Fancg (+/-)) mice utilized in these studies. Student's t-test and one-way ANOVA were used to evaluate statistical differences between WT and Fancg (-/-) cells. Statistical significance was defined as P values less than 0.05. RESULTS:Fancg deficient (Fancg (-/-)) mesenchymal stem/progenitor cells (MSPCs) produce significant lower levels of KC, an interleukin-8 (IL-8) related chemoattractant protein in rodents, as compared to wild type cells. Combinatorial administration of KC and G-CSF significantly increased the mobilization of hematopoietic stem/progenitor cells (HSPCs) in Fancg (-/-) mice. CONCLUSIONS: In summary, our results suggest that KC/IL-8 could be proved useful in the synergistic mobilization of FA HSPCs in combination with G-CSF.
Authors: Graça A Justo; Marco A Bitencourt; Ricardo Pasquini; Morgana T L Castelo-Branco; Vivian M Rumjanek Journal: Cytokine Date: 2013-09-07 Impact factor: 3.861
Authors: Anna C Pulliam; M Joe Hobson; Samantha L Ciccone; Yan Li; Shi Chen; Edward F Srour; Feng-Chun Yang; Hal E Broxmeyer; D Wade Clapp Journal: Exp Hematol Date: 2008-05-20 Impact factor: 3.084
Authors: T Watanabe; Y Kawano; S Kanamaru; T Onishi; S Kaneko; Y Wakata; R Nakagawa; A Makimoto; Y Kuroda; Y Takaue; J E Talmadge Journal: Blood Date: 1999-02-15 Impact factor: 22.113
Authors: Agata Smogorzewska; Shuhei Matsuoka; Patrizia Vinciguerra; E Robert McDonald; Kristen E Hurov; Ji Luo; Bryan A Ballif; Steven P Gygi; Kay Hofmann; Alan D D'Andrea; Stephen J Elledge Journal: Cell Date: 2007-04-05 Impact factor: 41.582