First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
Department of Biomedical Informatics, Center for Preventive Medicine and Digital Health, Mannheim, Germany.
Pathol Oncol Res. 2022 Mar 14;28:1610217. doi: 10.3389/pore.2022.1610217. eCollection 2022.
In myelofibrosis, pathologically enhanced extracellular matrix production due to aberrant cytokine signalling and result() in impaired hemopoiesis. Disease progression is still determined by detecting reticulin and collagen fibrosis with Gomori's silver impregnation. Here, we tested whether the expression growth related biomarkers L-NGFR/CD271, phospho-ERK1-2 and CXCL12 can be linked to the functional activation of bone marrow stromal cells during primary myelofibrosis progression. Immunoscores for all tested biomarkers showed varying strength of positive statistical correlation with the silver impregnation based myelofibrosis grades. The intimate relationship between spindle shaped stromal cells positive for all three markers and aberrant megakaryocytes was likely to reflect their functional cooperation. L-NGFR reaction was restricted to bone marrow stromal cells and revealed the whole length of their processes. Also, L-NGFR positive cells showed the most intersections, the best statistical correlations with myelofibrosis grades and the strongest interrater agreements. CXCL12 reaction highlighted stromal cell bodies and a weak extracellular staining in line with its constitutive release. Phospho-ERK1-2 reaction showed a similar pattern to CXCL12 in stromal cells with an additional nuclear staining in agreement with its role as a transcription factor. Both -ERK1-2 and CXCL12 were also expressed at a moderate level in sinus endothelial cells. Connexin 43 gap junction communication channels, known to be required for CXCL12 release to maintain stem cell niche, were also expressed progressively in the myelofibrotic stromal network as a support of compartmental functions. Our results suggest that, diverse growth related pathways are activated in the functionally coupled bone marrow stromal cells during myelofibrosis progression. L-NGFR expression can be a useful biological marker of stromal cell activation which deserves diagnostic consideration for complementing Gomori's silver impregnation.
在骨髓纤维化中，由于异常细胞因子信号导致细胞外基质过度产生，从而导致造血功能受损。疾病的进展仍然取决于用 Gomori 银染检测网状纤维和胶原纤维纤维化。在这里，我们测试了生长相关生物标志物 L-NGFR/CD271、磷酸化 ERK1-2 和 CXCL12 的表达是否可以与原发性骨髓纤维化进展过程中骨髓基质细胞的功能激活相关联。所有测试生物标志物的免疫评分均显示与基于银染的骨髓纤维化分级呈正相关。所有三种标志物均呈阳性的梭形基质细胞与异常巨核细胞之间的密切关系可能反映了它们的功能合作。L-NGFR 反应仅限于骨髓基质细胞，并显示其整个过程。此外，L-NGFR 阳性细胞显示出与骨髓纤维化分级的最多交点、最强的统计相关性和最强的评分者间一致性。CXCL12 反应突出了基质细胞体和与其组成性释放一致的弱细胞外染色。磷酸化 ERK1-2 反应在基质细胞中表现出与 CXCL12 相似的模式，另外还有核染色，这与其作为转录因子的作用一致。ERK1-2 和 CXCL12 在窦内皮细胞中也以中等水平表达。已知缝隙连接蛋白 43 间隙连接通讯通道对于维持干细胞龛所需的 CXCL12 释放是必需的，它们在骨髓纤维化基质网络中也呈渐进式表达，以支持隔室功能。我们的研究结果表明，在骨髓纤维化进展过程中，功能偶联的骨髓基质细胞中激活了多种生长相关途径。L-NGFR 表达可以作为基质细胞激活的有用生物学标志物，值得考虑用于补充 Gomori 银染。
