Monday, February 28, 2011

Hyaluronan Synthase 1 to be tall?

LSJL upregulates hyaluronan synthase 1 by 4.1 fold.

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. HA depletion reduces the ability of the microenvironment to support HSPC, and HA [is] a necessary regulatory element in the structure of the hematopoietic microenvironment."

So the increase in HAS1 may be to increase hematopoiesis (formation of blood cells).

"LTBMC extend these results to show that HMW HA also increased production of several chemokines, including MIP-1α, MCP-1, CXCL16, SDF-1, and RANTES. In addition, HMW[High Molecular Weight] HA stimulated the production of growth factors including G-CSF, IGFBP-3, IL-12, LIX, IL-9, KC, and soluble VCAM-1"

Hyaluronan is required for cranial neural crest cells migration and craniofacial development.

"hyaluronan synthesized by Has1 and Has2 is necessary for the proper development of the visceral skeleton"

"While cell movement in vitro is promoted by hyaluronan, it is inhibited by degrading the hyaluronan itself or by blocking its binding to both of the hyaluronan receptors CD44 and RHAMM"

"CD44 could mediate the hyaluronan instructive effect that initiates signaling pathways and thus promotes NCC movements."

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