Kindlin-3-mediated integrin adhesion is dispensable for quiescent but essential for activated hematopoietic stem cells.
Hematopoietic stem cells (HSCs) generate highly dividing hematopoietic progenitor cells (HPCs), which produce all blood cell lineages. HSCs are usually quiescent, retained by integrins in specific niches, and become activated when the pools of HPCs decrease. We report that Kindlin-3-mediated integrin activation controls homing of HSCs to the bone marrow (BM) and the retention of activated HSCs and HPCs but not of quiescent HSCs in their BM niches. Consequently, Kindlin-3-deficient HSCs enter quiescence and remain in the BM when cotransplanted with wild-type hematopoietic stem and progenitor cells (HSPCs), whereas they are hyperactivated and lost in the circulation when wild-type HSPCs are absent, leading to their exhaustion and reduced survival of recipients. The accumulation of HSPCs in the circulation of leukocyte adhesion deficiency type III patients, who lack Kindlin-3, underlines the conserved functions of Kindlin-3 in man and the importance of our findings for human disease.
Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
Raphael
R
Ruppert
Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
Markus
M
Moser
Walter Brendel Center of Experimental Medicine, Ludwig Maximilian University, 80539 Munich, Germany.
Markus
M
Sperandio
Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
Emanuel
E
Rognoni
Medical Clinic and Policlinic I, Klinikum der Universität, 80336 Munich, Germany.
Martin
M
Orban
Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
Wen-Hsin
WH
Liu
Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, 89081 Ulm, Germany.
Ansgar S
AS
Schulz
Third Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität, 80337 Munich, Germany.
Robert A J
RA
Oostendorp
Medical Clinic and Policlinic I, Klinikum der Universität, 80336 Munich, Germany.
Steffen
S
Massberg
Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany faessler@biochem.mpg.de.
Reinhard
R
Fässler
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007223:Infant; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*
D003598:Cytoskeletal Proteins; C477322:FERMT3 protein, human; D016023:Integrins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C527818:kindlin-3 protein, mouse