Urbanek Konrad, Cesselli Daniela, Rota Marcello, Nascimbene Angelo, De Angelis Antonella, Hosoda Toru, Bearzi Claudia, Boni Alessandro, Bolli Roberto, Kajstura Jan, Anversa Piero, Leri Annarosa
Cardiovascular Research Institute, Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.
Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9226-31. doi: 10.1073/pnas.0600635103. Epub 2006 Jun 5.
Cardiac stem cells (CSCs) have been identified in the adult heart, but the microenvironment that protects the slow-cycling, undifferentiated, and self-renewing CSCs remains to be determined. We report that the myocardium possesses interstitial structures with the architectural organization of stem cell niches that harbor long-term BrdU-retaining cells. The recognition of long-term label-retaining cells provides functional evidence of resident CSCs in the myocardium, indicating that the heart is an organ regulated by a stem cell compartment. Cardiac niches contain CSCs and lineage-committed cells, which are connected to supporting cells represented by myocytes and fibroblasts. Connexins and cadherins form gap and adherens junctions at the interface of CSCs-lineage-committed cells and supporting cells. The undifferentiated state of CSCs is coupled with the expression of alpha(4)-integrin, which colocalizes with the alpha(2)-chain of laminin and fibronectin. CSCs divide symmetrically and asymmetrically, but asymmetric division predominates, and the replicating CSC gives rise to one daughter CSC and one daughter committed cell. By this mechanism of growth kinetics, the pool of primitive CSCs is preserved, and a myocyte progeny is generated together with endothelial and smooth muscle cells. Thus, CSCs regulate myocyte turnover that is heterogeneous across the heart, faster at the apex and atria, and slower at the base-midregion of the ventricle.
心脏干细胞（CSCs）已在成体心脏中被鉴定出来，但保护缓慢循环、未分化且自我更新的CSCs的微环境仍有待确定。我们报告称，心肌具有间质结构，其具有干细胞龛的组织结构，其中含有长期保留5-溴脱氧尿苷（BrdU）的细胞。对长期标记保留细胞的识别为心肌中驻留CSCs提供了功能证据，表明心脏是一个受干细胞区室调节的器官。心脏龛包含CSCs和定向分化细胞，它们与以心肌细胞和成纤维细胞为代表的支持细胞相连。连接蛋白和钙黏着蛋白在CSCs-定向分化细胞与支持细胞的界面处形成缝隙连接和黏着连接。CSCs的未分化状态与α(4)-整合素的表达相关联，α(4)-整合素与层粘连蛋白和纤连蛋白的α(2)链共定位。CSCs进行对称分裂和不对称分裂，但不对称分裂占主导，正在复制的CSC产生一个子代CSC和一个子代定向分化细胞。通过这种生长动力学机制，原始CSCs库得以保留，并产生了心肌细胞后代以及内皮细胞和平滑肌细胞。因此，CSCs调节心肌细胞更新，这种更新在心脏各部位是异质性的，在心脏尖部和心房较快，而在心室基部-中部较慢。
