Hyaluronan expressed by the hematopoietic microenvironment is required for bone marrow hematopoiesis.
The contribution of hyaluronan (HA) to the regulatory network of the hematopoietic microenvironment was studied using knock-out mice of three hyaluronan synthase genes (Has1, Has2, and Has3). The number of hematopoietic progenitors was decreased in bone marrow and increased in extramedullary sites of Prx1-Cre;Has2(flox/flox);Has1(-/-);Has3(-/-) triple knock-out (tKO) mice as compared with wild type (WT) and Has1(-/-);Has3(-/-) double knock-out (dKO) mice. In line with this observation, decreased hematopoietic activity was observed in long term bone marrow cultures (LTBMC) from tKO mice, whereas the formation of the adherent layer and generation of hematopoietic cells in WT and dKO cultures was not different. 4-Methylumbelliferone (4MU) was used to pharmacologically inhibit the production of HA in LTBMC. Treatment with 4MU inhibited HA synthesis, decreased expression of HAS2 and HAS3, and eliminated hematopoiesis in LTBMC, and this effect was alleviated by the addition of exogenous HA. Exogenous HA also augmented the cell motility in LTBMC, which correlated with the HA-stimulated production of chemokines and growth factors. Conditioned media from HA-induced LTBMC enhanced the chemotaxis of hematopoietic stem/progenitor cells (HSPC) in response to SDF-1. Exposure of endothelial cells to 4MU decreased their ability to support HSPC rolling and adhesion. In addition, migration of transplanted HSPC into the marrow of 4MU-pretreated mice was lower than in untreated mice. Collectively, the results suggest that HA depletion reduces the ability of the microenvironment to support HSPC, and confirm a role for HA as a necessary regulatory element in the structure of the hematopoietic microenvironment.
Torrey Pines Institute for Molecular Studies, San Diego, California 92121, USA.
Valentina
V
Goncharova
Naira
N
Serobyan
Shinji
S
Iizuka
Ingrid
I
Schraufstatter
Audrey
A
de Ridder
Tatiana
T
Povaliy
Valentina
V
Wacker
Naoki
N
Itano
Koji
K
Kimata
Irina A
IA
Orlovskaja
Yu
Y
Yamaguchi
Sophia
S
Khaldoyanidi
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000235:genetics / Q000378:metabolism*; D006923:Hymecromone / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D055153:Stem Cell Niche / Q000187:drug effects / Q000502:physiology*
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D006923:Hymecromone; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C101754:HAS2 protein, human; C105458:HAS3 protein, human; C491099:Has2 protein, mouse; C491356:Has3 protein, mouse; D000076002:Hyaluronan Synthases