1.Dept. of Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
J Leukoc Biol. 2014 Apr;95(4):677-88. doi: 10.1189/jlb.0313147. Epub 2013 Dec 6.
Heparanase is an endo-β-glucuronidase that specifically cleaves the saccharide chains of HSPGs, important structural and functional components of the ECM. Cleavage of HS leads to loss of the structural integrity of the ECM and release of HS-bound cytokines, chemokines, and bioactive angiogenic- and growth-promoting factors. Our previous study revealed a highly significant correlation of HPSE gene SNPs rs4693608 and rs4364254 and their combination with the risk of developing GVHD. We now demonstrate that HPSE is up-regulated in response to pretransplantation conditioning, followed by a gradual decrease thereafter. Expression of heparanase correlated with the rs4693608 HPSE SNP before and after conditioning. Moreover, a positive correlation was found between recipient and donor rs4693608 SNP discrepancy and the time of neutrophil and platelet recovery. Similarly, the discrepancy in rs4693608 HPSE SNP between recipients and donors was found to be a more significant factor for the risk of aGVHD than patient genotype. The rs4693608 SNP also affected HPSE gene expression in LPS-treated MNCs from PB and CB. Possessors of the AA genotype exhibited up-regulation of heparanase with a high ratio in the LPS-treated MNCs, whereas individuals with genotype GG showed down-regulation or no effect on HPSE gene expression. HPSE up-regulation was mediated by TLR4. The study emphasizes the importance of rs4693608 SNP for HPSE gene expression in activated MNCs, indicating a role in allogeneic stem cell transplantation, including postconditioning, engraftment, and GVHD.
肝素酶是一种内切β-葡糖醛酸酶，可特异性切割 HSPGs 的糖链，HSPGs 是 ECM 的重要结构和功能成分。HS 的切割导致 ECM 的结构完整性丧失，并释放与 HS 结合的细胞因子、趋化因子和生物活性血管生成和促生长因子。我们之前的研究表明，HPSE 基因 SNP rs4693608 和 rs4364254 及其与 GVHD 发生风险的组合高度相关。我们现在证明，HPSE 在移植前预处理后上调，随后逐渐下降。肝素酶的表达与预处理前后 rs4693608 HPSE SNP 相关。此外，在接受者和供体 rs4693608 SNP 差异与中性粒细胞和血小板恢复时间之间发现了正相关。同样，发现受者和供体 rs4693608 HPSE SNP 差异是移植物抗宿主病风险的更重要因素，而不是患者基因型。rs4693608 SNP 还影响 PB 和 CB 中 LPS 处理的 MNC 中的 HPSE 基因表达。AA 基因型的个体在 LPS 处理的 MNC 中表现出肝素酶的上调，而 GG 基因型的个体则表现出下调或对 HPSE 基因表达无影响。HPSE 上调是由 TLR4 介导的。该研究强调了 rs4693608 SNP 对激活的 MNC 中 HPSE 基因表达的重要性，表明其在异基因干细胞移植中发挥作用，包括移植后、植入和 GVHD。
