Tan S J, Fang J Y, Wu Y, Yang Z, Liang G, Han B
Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA.
Nimni-Cordoba Tissue Engineering and Drug Discovery Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, Keck Medical School, University of Southern California, Los Angeles, CA.
Sci Rep. 2015 Nov 9;5:16333. doi: 10.1038/srep16333.
Efficiency of cell-based tissue engineering and regenerative medicine has been limited by inadequate cellular responses to injury because of aging and poor controllability of cellular interactions. Since cell progression is under a tight epigenetic regulation, epigenetic modulators such as 5-azacytidine (5-Aza-CR) have been utilized to facilitate reprogramming and development of somatic cells in 2-dimensional (2-D) settings. Nonetheless, progression of a specific tissue lineage toward the terminal phenotype is dependent not only on the genomic potential, but also on the microenvironment cues that are beyond the capability of 2-D approaches. In this study, we investigated the combined effects of matrices of variable rigidities and the treatment with the epigenetic modulator 5-Aza-CR on reprogramming adipose-derived stromal cells (ADSCs) into myoblast-like cells by utilizing tunable transglutaminase cross-linked gelatin (Col-Tgel) in vitro and in vivo. Our experiments demonstrated that cellular plasticity and trans-differentiation were significantly enhanced when ADSCs were treated with an effective dose of 5-Aza-CR (1.25 to 12.5 ng) in the optimal myogenic matrix (15 ± 5 kPa Col-Tgel). Our findings suggest that both physical signals and chemical milieu are critical for the regulation of cellular responses.
基于细胞的组织工程和再生医学的效率一直受到限制，原因是由于衰老导致细胞对损伤的反应不足以及细胞相互作用的可控性较差。由于细胞进程受到严格的表观遗传调控，表观遗传调节剂如5-氮杂胞苷（5-Aza-CR）已被用于促进二维（2-D）环境中体细胞的重编程和发育。然而，特定组织谱系向终末表型的进展不仅取决于基因组潜力，还取决于二维方法无法涵盖的微环境线索。在本研究中，我们通过在体外和体内利用可调转谷氨酰胺酶交联明胶（Col-Tgel），研究了可变硬度基质和表观遗传调节剂5-Aza-CR处理对将脂肪来源的基质细胞（ADSCs）重编程为成肌样细胞的联合作用。我们的实验表明，当在最佳成肌基质（15±5kPa Col-Tgel）中用有效剂量的5-Aza-CR（1.25至12.5 ng）处理ADSCs时，细胞可塑性和转分化显著增强。我们的研究结果表明，物理信号和化学环境对于调节细胞反应都至关重要。
