Regulation of adult hematopoiesis by the a disintegrin and metalloproteinase 10 (ADAM10).
Adult hematopoiesis requires tightly regulated cell-cell interactions between hematopoietic cells and the bone marrow stromal microenvironment. We addressed the question if the ectodomain sheddase ADAM10 is essential to regulate adult hematopoiesis. Induced ADAM10 deletion in hematopoietic cells resulted in morphological and histological abnormalities that resemble an unclassified myeloproliferative disorder (MPD). The MPD was characterized by an expansion of granulocytic subpopulations and their infiltration of peripheral hematopoietic tissues, the development of hepatosplenomegaly with extramedullary erythropoiesis, lymphnodepathy and death of the mice around 20weeks after induction. ADAM10 expression analysis during the different stages of the MPD revealed that non-targeted hematopoietic cells repopulated the immune system of the ADAM10-deficient mice. Examination of mice with a myeloid- or epidermis-specific deletion of ADAM10 and bone marrow transplantation (BMT) experiments indicated that the development of the MPD can be triggered by non-cell autonomous effects. We found that plasma levels of clinical markers for MPD such as G-CSF, TIMP-1 and IL-16 were significantly elevated in ADAM10-deficient mice. Our findings indicate that a tightly controlled ADAM10 expression is needed to balance hematopoietic cell-fate decisions in adult mice.
Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany.
Silvio
S
Weber
Sebastian
S
Wetzel
Johannes
J
Prox
Tobias
T
Lehmann
Janna
J
Schneppenheim
Marjo
M
Donners
Paul
P
Saftig
D051722:ADAM Proteins / Q000235:genetics / Q000502:physiology*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001853:Bone Marrow / Q000201:enzymology / Q000473:pathology; D019483:Disintegrins / Q000235:genetics / Q000502:physiology*; D004485:Eczema / Q000235:genetics / Q000473:pathology; D005260:Female; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology*; D006529:Hepatomegaly / Q000235:genetics / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000201:enzymology / Q000473:pathology; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000473:pathology; D013163:Splenomegaly / Q000235:genetics / Q000473:pathology; D017154:Stromal Cells / Q000201:enzymology / Q000473:pathology; D013922:Thrombocytosis / Q000235:genetics / Q000473:pathology
D019483:Disintegrins; D008565:Membrane Proteins; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse
ADAM proteases; Ectodomain shedding; Granulopoesis; Myeloproliferative disorder