Reeser Rachel S, Salazar Alyssa K, Prutton Kendra M, Roede James R, VeDepo Mitchell C, Jacot Jeffrey G
Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 USA.
Linda Crnic Institute for Down Syndrome, Colorado, Aurora, CO 80045 USA.
Cell Mol Bioeng. 2024 Jan 3;17(1):25-34. doi: 10.1007/s12195-023-00791-x. eCollection 2024 Feb.
Individuals with Down syndrome (DS) are 2000 times more likely to develop a congenital heart defect (CHD) than the typical population Freeman et al. in Am J Med Genet 80:213-217 (1998). The majority of CHDs in individuals with DS characteristically involve the atrioventricular (AV) canal, including the valves and the atrial or ventricular septum. Type VI collagen (COLVI) is the primary structural component in the developing septa and endocardial cushions, with two of the three genes encoding for COLVI located on human chromosome 21 and upregulated in Down syndrome (von Kaisenberg et al. in Obstet Gynecol 91:319-323, 1998; Gittenberger-De Groot et al. in Anatom Rec Part A 275:1109-1116, 2023).
To investigate the effect of COLVI dosage on cardiomyocytes with trisomy 21, induced pluripotent stem cells (iPSC) from individuals with DS and age- and sex-matched controls were differentiated into cardiomyocytes (iPSC-CM) and plated on varying concentrations of COLVI.
Real time quantitative PCR showed decreased expression of cardiac-specific genes of DS iPSC-CM lines compared to control iPSC-CM. As expected, DS iPSC-CM had increased expression of genes on chromosome 21, including , , as well as genes not located on chromosome 21, namely , and . We found that higher concentrations of COLVI result in decreased proliferation and migration of DS iPSC-CM, but not control iPSC-CM.
These results suggest that the increased expression of COLVI in DS may result in lower migration-driven elongation of endocardial cushions stemming from lower cell proliferation and migration, possibly contributing to the high incidence of CHD in the DS population.
The online version contains supplementary material available at 10.1007/s12195-023-00791-x.
唐氏综合征（DS）患者患先天性心脏病（CHD）的可能性是普通人群的2000倍（弗里曼等人，《美国医学遗传学杂志》80:213 - 217，1998年）。DS患者中的大多数CHD典型地累及房室（AV）通道，包括瓣膜以及心房或心室间隔。VI型胶原蛋白（COLVI）是发育中的间隔和心内膜垫的主要结构成分，编码COLVI的三个基因中的两个位于人类21号染色体上，且在唐氏综合征中上调（冯·凯森贝格等人，《妇产科学》91:319 - 323，1998年；吉滕伯格 - 德·格鲁特等人，《解剖学记录A部分》275:1109 - 1116，2023年）。
为了研究COLVI剂量对21三体心肌细胞的影响，将来自DS患者以及年龄和性别匹配对照的诱导多能干细胞（iPSC）分化为心肌细胞（iPSC - CM），并接种在不同浓度的COLVI上。
实时定量PCR显示，与对照iPSC - CM相比，DS iPSC - CM系的心脏特异性基因表达降低。正如预期的那样，DS iPSC - CM中21号染色体上的基因表达增加，包括 、 ，以及不在21号染色体上的基因，即 、 和 。我们发现，较高浓度的COLVI会导致DS iPSC - CM的增殖和迁移减少，但对照iPSC - CM不受影响。
这些结果表明，DS中COLVI表达增加可能导致心内膜垫因细胞增殖和迁移降低而由迁移驱动的伸长减少，这可能是DS人群中CHD高发的原因。
在线版本包含可在10.1007/s12195 - 023 - 00791 - x获取的补充材料。
