Activated hepatic stellate cells are dependent on self collagen, cleaved by membrane type 1-matrix metalloproteinase for their growth [Glycobiology and Extracellular Matrices]

May 27th, 2014 by Birukawa, N. K., Murase, K., Sato, Y., Kosaka, A., Yoneda, A., Nishita, H., Fujita, R., Nishimura, M., Ninomiya, T., Kajiwara, K., Miyazaki, M., Nakashima, Y., Ota, S., Murakami, Y., Tanaka, Y., Minomi, K., Tamura, Y., Niitsu, Y.

Stellate cells are distributed throughout organs where upon chronic damage, they become activated and proliferate to secrete collagen, that results in organ fibrosis. An intriguing property of hepatic stellate cells (HSCs) is that they undergo apoptosis when collagen is resolved by either stopping tissue damage or by treatment even though the mechanisms are unknown. Here we disclose the fact that HSCs, normal diploid cells acquired dependence on collagen for their growth during the transition from quiescent to active states. The intra-molecular RGD motifs of collagen were exposed by cleavage with their own membrane type 1-matrix metalloproteinase (MT1-MMP). The following evidences support this conclusion. When rat activated HSCs (aHSCs) were transduced with siRNA against the collagen specific chaperone, gp46 to inhibit collagen secretion, the cells underwent autophagy followed by apoptosis. Concomitantly, the growth of aHSCs was suppressed, while that of quiescent HSCs was not. These in vitro results are compatible with in vivo observation that apoptosis of aHSCs was induced in cirrhotic livers of rats treated with siRNAgp46. siRNA against MT1-MMP and addition of tissue inhibitor of metalloproteinase (TIMP)-2 which mainly inhibits MT1-MMP, also significantly suppressed the growth of aHSCs in vitro. Both RGD inhibitors, echistatin and GRGDS peptides, and siRNA against RGD receptor, αVβ1, resulted in inhibition of aHSCs growth. Transducing of siRNAs against gp46, αVβ1 and MT1-MMP to aHSCs inhibited survival signal of PI3K/AKT/IKB. These results should provide novel antifibrosis strategies.
  • Posted in Journal of Biological Chemistry, Publications
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