Rac2-deficient hematopoietic stem cells show defective interaction with the hematopoietic microenvironment and long-term engraftment failure.
The hematopoietic-specific Rho GTPase, Rac2, regulates a variety of cellular functions including cell shape changes, motility, integrin-dependent adhesion, and apoptosis. In the study reported here, we demonstrate that wild-type (WT) hematopoietic stem cells/progenitors (HSC/P) preferentially engraft in nonablated Rac2(-/-) bone marrow. In addition, primitive Rac2(-/-) HSC/P transplanted into lethally irradiated WT recipients showed a significant competitive defect compared with WT cells. These defects appeared to be related to HSC/P-intrinsic defective microenvironment interactions, since Rac2(-/-) cells showed less adhesion to the femur bone marrow density 1 (FBMD-1) stromal cell line, a lower frequency of cobblestone area-forming cells, and lower performance in long-term marrow cultures in vitro when compared with WT cells. In contrast, primitive Rac2(-/-) hematopoietic cells exhibited normal progenitor colony formation in semisolid medium in vitro and normal proliferation in the steady state in vivo when compared with WT cells. Taken together, these data suggest that Rac2(-/-) stem/progenitor cells exhibit abnormal interaction with the hematopoietic microenvironment, which leads to defective long-term engraftment.
Jansen
Michael
M
Division of Experimental Hematology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45215, USA.
Yang
Feng-Chun
FC
Cancelas
José A
JA
Bailey
Jeff R
JR
Williams
David A
DA
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D002453:Cell Cycle / Q000235:genetics; D002460:Cell Line; D019070:Cell Lineage; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D005260:Female; D006085:Graft Survival / Q000235:genetics / Q000502:physiology*; D006133:Growth Substances / Q000494:pharmacology; D006410:Hematopoiesis / Q000502:physiology*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D008198:Lymph Nodes / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D013154:Spleen / Q000166:cytology; D017154:Stromal Cells / Q000166:cytology; D014916:Whole-Body Irradiation; D020744:rac GTP-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D000097766:RAC2 GTP-Binding Protein
D006133:Growth Substances; D020744:rac GTP-Binding Proteins; D000097766:RAC2 GTP-Binding Protein