Tang Ying, Cheng Jiaxi, Huang Cynthia, Qiu Ping, Li Jingxin, Chen Yuqing Eugene, Mizrak Dogukan, Yang Bo
Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, United States.
Second Xiangya Hospital, Central South University, Changsha 410011, China.
Stem Cells Transl Med. 2025 Mar 18;14(3). doi: 10.1093/stcltm/szae101.
Pathogenic variants in canonical transforming growth factor β (TGFβ) signaling genes predispose patients to thoracic aortic aneurysm and dissection (TAAD), predominantly in aortic root. Although TAAD pathogenesis associated with TGFβ receptor defects is well characterized, distinct and redundant mechanisms of TGFβ isoforms in TAAD incidence and severity remain elusive.
Here we examined the biological role of TGFB2 in smooth muscle cell (SMC) differentiation and investigated how TGFB2 defects can lead to regional TAAD manifestations.
To characterize the role of TGFB2 in SMC differentiation and function, we employed human-induced pluripotent stem cell (hiPSC)-derived SMC differentiation, CRISPR/Cas9 gene editing, three-dimensional SMC constructs, and human aortic tissue samples.
Despite the similar effects of different TGFβ isoforms on hiPSC-derived SMC differentiation, siRNA experiments revealed that TGFB2 distinctively displays TGFBR3 dependence for signal transduction, an understudied TGFβ receptor in TAAD. Molecular evaluation of different thoracic aorta regions suggested TGFB2 and TGFBR3 enrichment in the aortic root tunica media. TGFB2 haploinsufficiency (TGFB2KO/+) and TGFB2 neutralization impaired the differentiation of second heart field-derived SMCs. TGFBR3KO/KO prevented the molecular rescue of TGFB2KO/+ by TGFB2 supplementation indicating the involvement of TGFBR3 in TGFB2-mediated SMC differentiation. Lastly, a missense TGFB2 variant (TGFB2G276R/+) caused mechanical defects in SMC tissue ring constructs that were rescued by TGFB2 supplementation or genetic correction.
Our data suggests the distinct regulation and action of TGFB2 in SMCs populating the aortic root, while redundant activities of TGFβ isoforms provide implications about the milder TAAD aggressiveness of pathogenic TGFB2 variants.
经典转化生长因子β（TGFβ）信号基因中的致病变异使患者易患胸主动脉瘤和夹层（TAAD），主要发生在主动脉根部。虽然与TGFβ受体缺陷相关的TAAD发病机制已得到充分表征，但TGFβ亚型在TAAD发生率和严重程度方面的独特和冗余机制仍不清楚。
在此，我们研究了TGFB2在平滑肌细胞（SMC）分化中的生物学作用，并探讨了TGFB2缺陷如何导致局部TAAD表现。
为了表征TGFB2在SMC分化和功能中的作用，我们采用了人诱导多能干细胞（hiPSC）衍生的SMC分化、CRISPR/Cas9基因编辑、三维SMC构建体和人主动脉组织样本。
尽管不同TGFβ亚型对hiPSC衍生的SMC分化有相似作用，但小干扰RNA实验表明，TGFB2在信号转导中独特地显示出对TGFBR3的依赖性，TGFBR3是TAAD中一个研究较少的TGFβ受体。对不同胸主动脉区域的分子评估表明，TGFB2和TGFBR3在主动脉根中膜富集。TGFB2单倍体不足（TGFB2KO/+）和TGFB2中和损害了第二心脏场衍生的SMC的分化。TGFBR3KO/KO阻止了通过补充TGFB2对TGFB2KO/+的分子挽救，表明TGFBR3参与了TGFB2介导的SMC分化。最后，一个错义TGFB2变体（TGFB2G276R/+）在SMC组织环构建体中导致机械缺陷，通过补充TGFB2或基因校正得以挽救。
我们的数据表明TGFB2在主动脉根中的SMC中具有独特的调节和作用，而TGFβ亚型的冗余活动提示了致病性TGFB2变体的TAAD侵袭性较轻。
