Role of the monomeric GTPase Rho in hematopoietic progenitor cell migration and transplantation.
To investigate the role of the monomeric guanosine triphosphatase (GTPase) Rho on migration of hematopoietic progenitor cells (HPC), we employed different clostridial toxins which inhibit the Rho family of GTPases. Pretreatment with C2I-C3, a cell-accessible C3 transferase fusion protein that targets Rho, increased chemokinetic migration of the factor-dependent multipotent cell line Factor Dependent Cell Paterson with mixed lineage differentiation potential (FDCP-mix) and of primary lineage marker-depleted HPC in vitro. In contrast, treatment with lethal toxin (LT) from Clostridium sordellii, which predominantly inactivates Rac, and with toxin B from C. difficile, which inactivates Rho, Rac and Cdc42, decreased in vitro migration. When HPC pretreated with LT or toxin B were transplanted into mice, homing to the bone marrow was impaired, whereas C2I-C3 treatment did not alter HPC homing. However, in a competitive hematopoietic repopulation experiment in C57BL/6 mice, pretreatment of bone marrow cells with any of the inhibitors, including the Rho inhibitor C2I-C3, resulted in suppressed donor-type hematopoiesis. Our data indicate that whereas Rac supports HPC cell cycling, migration, short-term homing and hematopoietic regeneration, Rho coordinates down-regulation of HPC migration and is required for hematopoietic regeneration.
Göttig
Stephan
S
Institute of Transfusion Medicine and Immune Hematology, German Red Cross Blood Center, Johann Wolfgang Goethe University, Frankfurt am Main, Germany.
Möbest
Dietrich
D
Rüster
Brigitte
B
Grace
Bithiah
B
Winter
Sylvia
S
Seifried
Erhard
E
Gille
Jens
J
Wieland
Thomas
T
Henschler
Reinhard
R
D036002:ADP Ribose Transferases / Q000378:metabolism; D000818:Animals; D001905:Botulinum Toxins / Q000494:pharmacology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism*
D004791:Enzyme Inhibitors; D036002:ADP Ribose Transferases; D001905:Botulinum Toxins; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins