IPF肺含有间充质祖细胞（MPC），这些细胞在体内表现出致癌信号的持久激活和细胞自主纤维化性。先前的工作在 IPF MPC 中发现了 CD44/Brg1/PRMT5 核调节模块，该模块增加了正调节多能性和自我更新的基因的表达。悬而未决的是 IPF MPC 如何逃避自我更新的负面监管。在这里，我们试图找出在 IPF MPC 中禁用自我更新负调节的机制。我们证明肿瘤抑制基因 rbl1 和 pten 的表达在 IPF MPC 中降低。该机制涉及 CD44 促进染色质重塑蛋白 Brg1 与组蛋白修饰甲基转移酶 PRMT5 的关联。 Brg1 增强染色质可及性，导致 PRMT5 介导的 rbl1 和 pten 基因上的 H3R8 和 H4R3 甲基化，从而抑制其表达。 Brg1 或 PRMT5 的基因敲低或药理抑制可恢复 RBL1 和 PTEN 的表达，减少体外 IPF MPC 的自我更新，并抑制体内 IPF MPC 介导的肺纤维化。我们的研究表明，CD44/Brg1/PRMT5 调节模块不仅具有激活多能性和自我更新的正调节因子的功能，而且还具有抑制肿瘤抑制基因 rbl1 和 pten 的功能。这赋予了 IPF MPC 细胞自主自我更新的类似癌症的特性，为 IPF 中无情的纤维化进展提供了分子机制。

The IPF lung contains mesenchymal progenitor cells (MPCs) that display durable activation of oncogenic signaling and cell-autonomous fibrogenicity in vivo. Prior work identified a CD44/Brg1/PRMT5 nuclear regulatory module in IPF MPCs that increased expression of genes positively regulating pluripotency and self-renewal. Left unanswered is how IPF MPCs evade negative regulation of self-renewal. Here we sought to identify mechanisms disabling negative regulation of self-renewal in IPF MPCs. We demonstrate that expression of the tumor suppressor genes rbl1 and pten is decreased in IPF MPCs. The mechanism involves CD44-facilitated association of the chromatin remodeler Brg1 with the histone modifying methyltransferase PRMT5. Brg1 enhances chromatin accessibility leading to PRMT5-mediated methylation of H3R8 and H4R3 on the rbl1 and pten genes, repressing their expression. Genetic knock-down or pharmacological inhibition of either Brg1 or PRMT5 restored RBL1 and PTEN expression, reduced IPF MPC self-renewal in vitro and inhibited IPF MPC-mediated pulmonary fibrosis in vivo. Our studies indicate that the CD44/Brg1/PRMT5 regulatory module not only functions to activate positive regulators of pluripotency and self-renewal, but also functions to repress tumor suppressor genes rbl1 and pten. This confers IPF MPCs with the cancer-like property of cell-autonomous self-renewal providing a molecular mechanism for relentless fibrosis progression in IPF.