Identification of cardiac stem cells within mature cardiac myocytes

Cardiac stem cells are described in a number of mammalian species including humans. Cardiac stem cell clusters consisting of both lineage-negative and partially committed cells are generally identified between contracting cardiac myocytes. In the present study, c-kit⁺, Sca⁺, and Isl1⁺ stem cells were revealed to be located inside the sarcoplasm of cardiac myocytes in myocardial cell cultures derived from newborn, 20-, and 40-day-old rats. Intracellularly localized cardiac stem cells had a coating or capsule with a few pores that opened into the host cell sarcoplasm. The similar structures were also identified in the suspension of freshly isolated myocardial cells (ex vivo) of 20- and 40-day-old rats. The results from this study provide direct evidence for the replicative division of encapsulated stem cells, followed by their partial cardiomyogenic differentiation. The latter is substantiated by the release of multiple transient amplifying cells following the capsule rupture. In conclusion, functional cardiac stem cells can reside not only exterior to but also within cardiomyocytes.     

Modeling cell-in-cell structure into its biological significance

Although cell-in-cell structure was noted 100 years ago, the molecular mechanisms of ‘entering'' and the destination of cell-in-cell remain largely unclear. It takes place among the same type of cells (homotypic cell-in-cell) or different types of cells (heterotypic cell-in-cell). Cell-in-cell formation affects both effector cells and their host cells in multiple aspects, while cell-in-cell death is under more intensive investigation. Given that cell-in-cell has an important role in maintaining homeostasis, aberrant cell-in-cell process contributes to the etiopathology in humans. Indeed, cell-in-cell is observed in many pathological processes of human diseases. In this review, we intend to discuss the biological models of cell-in-cell structures under physiological and pathological status.     

Competition between human cells by entosis

Human carcinomas are comprised of complex mixtures of tumor cells that are known to compete indirectly for nutrients and growth factors. Whether tumor cells could also compete directly, for example by elimination of rivals, is not known. Here we show that human cells can directly compete by a mechanism of engulfment called entosis. By entosis, cells are engulfed, or cannibalized while alive, and subsequently undergo cell death. We find that the identity of engulfing (“winner”) and engulfed (“loser”) cells is dictated by mechanical deformability controlled by RhoA and actomyosin, where tumor cells with high deformability preferentially engulf and outcompete neighboring cells with low deformability in heterogeneous populations. We further find that activated Kras and Rac signaling impart winner status to cells by downregulating contractile myosin, allowing for the internalization of neighboring cells that eventually undergo cell death. Finally, we compute the energy landscape of cell-in-cell formation, demonstrating that a mechanical differential between winner and loser cells is required for entosis to proceed. These data define a mechanism of competition in mammalian cells that occurs in human tumors.     

Rac1促进异质型细胞叠套结构的形成

异质型细胞叠套结构（heterotypic cell-in-cell structure，heCICs）与肿瘤发生和发展密切相关，在生命科学研究中的重要性逐渐显露。Ras相关C3肉毒毒素底物1（Ras-related C3 botulinum toxin substrate 1，Rac1）属于经典的Rho GTP酶，在细胞骨架以及细胞运动中起到关键调控作用。为研究Rac1在heCICs形成中的作用和机制，利用活细胞示踪剂cell-tracker分别标记肿瘤细胞和免疫杀伤细胞，建立heCICs模型。利用Rac1抑制剂NSC23766抑制Rac1活性后发现，肿瘤细胞与免疫杀伤细胞之间的heCICs形成率显著降低。通过分子克隆技术获得重组质粒pQCXIP-Rac1-EGFP，进行病毒包装感染肿瘤细胞获得Rac1过表达细胞系。进一步检测Rac1过表达对heCICs形成能力的影响，结果表明，Rac1表达水平升高后，heCICs形成率显著升高。本研究显示Rac1具有促进heCICs形成的作用，这为Rac1作为细胞叠套相关疾病的药物治疗靶点奠定了研究基础。