Calcagno D M, Taghdiri N, Ninh V K, Mesfin J M, Toomu A, Sehgal R, Lee J, Liang Y, Duran J M, Adler E, Christman K L, Zhang K, Sheikh F, Fu Z, King K R
Department of Bioengineering, Jacobs School of Engineering, University of California San Diego, La Jolla, CA, USA.
These authors contributed equally: D.M. Calcagno, N. Taghdiri.
Nat Cardiovasc Res. 2022 Nov;1(11):1039-1055. doi: 10.1038/s44161-022-00160-3. Epub 2022 Nov 17.
The border zone (BZ) of the infarcted heart is a geographically complex and biologically enigmatic interface separating poorly perfused infarct zones (IZs) from remote zones (RZs). The cellular and molecular mechanisms of myocardial BZs are not well understood because microdissection inevitably combines them with uncontrolled amounts of RZs and IZs. Here, we use single-cell/nucleus RNA sequencing, spatial transcriptomics and multiplexed RNA fluorescence in situ hybridization to redefine the BZ based on cardiomyocyte transcriptomes. BZ1 ( ) forms a hundreds-of-micrometer-thick layer of morphologically intact cells adjacent to RZs that are detectable within an hour of injury. Meanwhile, BZ2 ( ) forms a near-single-cell-thick layer of morphologically distorted cardiomyocytes at the IZ edge that colocalize with matricellular protein-expressing myofibroblasts and express predominantly mechanotransduction genes. Surprisingly, mechanical injury alone is sufficient to induce BZ genes. We propose a 'loss of neighbor' hypothesis to explain how ischemic cell death mechanically destabilizes the BZ to induce its transcriptional response.
梗死心脏的边界区（BZ）是一个在地理上复杂且生物学上神秘的界面，它将灌注不良的梗死区（IZs）与远隔区（RZs）分隔开来。心肌BZ的细胞和分子机制尚未完全了解，因为显微切割不可避免地会将它们与数量不受控制的RZs和IZs混在一起。在这里，我们使用单细胞/细胞核RNA测序、空间转录组学和多重RNA荧光原位杂交，根据心肌细胞转录组重新定义BZ。BZ1（ ）在损伤后一小时内可检测到，它在与RZs相邻的位置形成一层数百微米厚的形态完整的细胞层。同时，BZ2（ ）在IZ边缘形成一层几乎单细胞厚的形态扭曲的心肌细胞层，这些细胞与表达基质细胞蛋白的肌成纤维细胞共定位，并主要表达机械转导基因。令人惊讶的是，仅机械损伤就足以诱导BZ基因。我们提出了一个“邻居丧失”假说，以解释缺血性细胞死亡如何通过机械方式破坏BZ的稳定性，从而诱导其转录反应。
