A defect in hematopoietic stem cell migration explains the nonrandom X-chromosome inactivation in carriers of Wiskott-Aldrich syndrome.

Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print-Electronic Cited Medium: Print ISSN: 0006-4971 (Print) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE

Publication: 2021- : [New York] : Elsevier
Original Publication: New York, Grune & Stratton [etc.]

Dosage Compensation, Genetic*; Chemotaxis/*physiology ; Hematopoietic Stem Cells/*cytology ; Hematopoietic Stem Cells/*physiology ; Proteins/*physiology ; Wiskott-Aldrich Syndrome/*genetics; Actins/antagonists & inhibitors ; Actins/metabolism ; Animals ; Bone Marrow Cells/cytology ; Bone Marrow Cells/physiology ; Cell Adhesion/physiology ; Chemokine CXCL12 ; Chemokines, CXC/pharmacology ; Collagen/metabolism ; Cytoskeleton/metabolism ; Female ; Fluorouracil/pharmacology ; Glutathione Transferase/metabolism ; Heterozygote ; Male ; Mice ; Mice, Knockout ; Proteins/genetics ; Proteins/metabolism ; Wiskott-Aldrich Syndrome/mortality ; Wiskott-Aldrich Syndrome/pathology ; Wiskott-Aldrich Syndrome Protein ; cdc42 GTP-Binding Protein/metabolism

A defect in cell trafficking and chemotaxis plays an important role in the immune deficiency observed in Wiskott-Aldrich syndrome (WAS). In this report, we show that marrow cells from WAS protein (WASP)-deficient mice also have a defect in chemotaxis. Serial transplantation and competitive reconstitution experiments demonstrated that marrow cells, including hematopoietic progenitors and stem cells (HSCs), have decreased homing capacities that were associated with a defect in adhesion to collagen. During development, HSCs migrate from the liver to the marrow and the spleen, prompting us to ask if a defect in HSC homing during development may explain the skewed X-chromosome inactivation in WAS carriers. Preliminary evidence has shown that, in contrast to marrow progenitor cells, fetal liver progenitor cells from heterozygous females had a random X-chromosome inactivation. When fetal liver cells from WASP-carrier females were injected into irradiated recipients, a nonrandom inactivation of the X-chromosome was found at the level of hematopoietic progenitors and HSCs responsible for the short- and long-term hematopoietic reconstitution. Therefore, the mechanism of the skewed X-chromosomal inactivation observed in WAS carriers may be related to a migration defect of WASP-deficient HSCs.

0 (Actins)
0 (Chemokine CXCL12)
0 (Chemokines, CXC)
0 (Cxcl12 protein, mouse)
0 (Proteins)
0 (Was protein, mouse)
0 (Wiskott-Aldrich Syndrome Protein)
9007-34-5 (Collagen)
EC 2.5.1.18 (Glutathione Transferase)
EC 3.6.5.2 (cdc42 GTP-Binding Protein)
U3P01618RT (Fluorouracil)

Date Created: 20030506 Date Completed: 20030911 Latest Revision: 20210206

20231215

10.1182/blood-2002-07-2099

12730112