Stem cell niches in the adult mouse heart
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 adherentj unctions at the interface of CSCs lineage-committed cells and supporting cells. The undifferentiated state of CSCs is coupled with the expression of a4-integrin,which colocalizes with the a2-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 preservedand 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.
[Proc Natl Acad Sci USA,2006;103(24), 9226-9231]
成年鼠心脏的干细胞微环境
在成人心脏中已经发现了心脏干细胞的存在,但是对于保护这些增殖缓慢、尚未分化但可自我更新的心脏干细胞的微环境，仍然有待研究。我们曾报道心肌层存在干细胞微环境组成的间质结构，其中包含可被溴脱氧尿嘧啶核苷长期标记的细胞。这些能长期被标记的细胞为心肌中存在心脏干细胞提供了功能依据，表明心脏是由干细胞层调控的器官。心脏微环境包含心脏干细胞和定向分化细胞，这两种细胞又与心肌细胞和成纤维细胞等支持细胞相连。
在干细胞定向分化细胞与支持细胞交界处，连接素和钙粘素构成缝隙连接和黏合连接。心脏干细胞未分化状态与a4整和素的表达同时存在，4整和素与层粘连蛋白和纤维连接蛋白的a2链定位于相同位置。心脏干细胞的分裂呈对称以及不对称两种方式，而不对称分裂居主要地位，心脏干细胞分裂后产生一个子代干细胞和一个定向分化的子细胞，通过这种生长动力学机制，原始的干细胞池得以维持,肌细胞和内皮细胞及平滑肌细胞也一起产生。因此，整个心脏中干细胞调节心肌细胞的增殖是不同步的，即在心尖和心房部位较快，在中央区的基底和心室部较慢。
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