PDF(Pubmed)
Abstract：
UNASSIGNED: 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).
UNASSIGNED: 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.
UNASSIGNED: 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 COL6A1, COL6A2, as well as genes not located on chromosome 21, namely COL6A3, HAS2 and HYAL2. We found that higher concentrations of COLVI result in decreased proliferation and migration of DS iPSC-CM, but not control iPSC-CM.
UNASSIGNED: 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.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s12195-023-00791-x.
UNASSIGNED: 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.
UNASSIGNED: 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 COL6A1, COL6A2, as well as genes not located on chromosome 21, namely COL6A3, HAS2 and HYAL2. We found that higher concentrations of COLVI result in decreased proliferation and migration of DS iPSC-CM, but not control iPSC-CM.
UNASSIGNED: 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.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s12195-023-00791-x.
摘要：
■患有唐氏综合症（DS）的人患先天性心脏病（CHD）的可能性是典型人群Freeman等人的2000倍。在AmJMedGenet80:213-217(1998)中。在具有DS特征的个体中，大多数CHD涉及房室（AV）管，包括瓣膜和心房或室间隔。VI型胶原蛋白（COLVI）是发展中的隔膜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，并在唐氏综合症中上调（vonKaisenberg等。在ObstetGynecol91：319-323，1998；Gittenberger-DeGroot等人。在AnatomRecA部分275：1109-1116，2023年)。
■为了研究COLVI剂量对21三体性心肌细胞的影响，将来自DS个体和年龄和性别匹配对照的诱导多能干细胞（iPSC）分化成心肌细胞（iPSC-CM）并铺在不同浓度的COLVI上。
■实时定量PCR显示，与对照iPSC-CM相比，DSiPSC-CM系的心脏特异性基因表达降低。不出所料,DSiPSC-CM在21号染色体上的基因表达增加，包括COL6A1，COL6A2，以及不位于21号染色体上的基因，即COL6A3，HAS2和HYAL2。我们发现，较高浓度的COLVI导致DSiPSC-CM的增殖和迁移减少，但不能控制iPSC-CM。
■这些结果表明，DS中COLVI表达的增加可能会导致由于较低的细胞增殖和迁移而引起的心内膜垫的较低迁移驱动的伸长，可能导致DS人群CHD的高发病率。
■在线版本包含补充材料，可在10.1007/s12195-023-00791-x获得。
■为了研究COLVI剂量对21三体性心肌细胞的影响，将来自DS个体和年龄和性别匹配对照的诱导多能干细胞（iPSC）分化成心肌细胞（iPSC-CM）并铺在不同浓度的COLVI上。
■实时定量PCR显示，与对照iPSC-CM相比，DSiPSC-CM系的心脏特异性基因表达降低。不出所料,DSiPSC-CM在21号染色体上的基因表达增加，包括COL6A1，COL6A2，以及不位于21号染色体上的基因，即COL6A3，HAS2和HYAL2。我们发现，较高浓度的COLVI导致DSiPSC-CM的增殖和迁移减少，但不能控制iPSC-CM。
■这些结果表明，DS中COLVI表达的增加可能会导致由于较低的细胞增殖和迁移而引起的心内膜垫的较低迁移驱动的伸长，可能导致DS人群CHD的高发病率。
■在线版本包含补充材料，可在10.1007/s12195-023-00791-x获得。
