Jiang Bin, Yan Li, Shamul James G, Hakun Maxwell, He Xiaoming
Fischell Department of Bioengineering, University of Maryland, College Park, Maryland 20742, United States.
Adv Ther (Weinh). 2020 Mar;3(3). doi: 10.1002/adtp.201900182. Epub 2020 Feb 3.
Myocardial infarction (MI) is a life-threatening disease resulting from irreversible death of cardiomyocytes (CMs) and weakening of the heart blood-pumping function. Stem cell-based therapies have been studied for MI treatment over the last two decades with promising outcome. In this review, we critically summarize the past work in this field to elucidate the advantages and disadvantages of treating MI using pluripotent stem cells (PSCs) including both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), adult stem cells, and cardiac progenitor cells. The main advantage of the latter is their cytokine production capability to modulate immune responses and control the progression of healing. However, human adult stem cells have very limited (if not 'no') capacity to differentiate into functional CMs in vitro or in vivo. In contrast, PSCs can be differentiated into functional CMs although the protocols for the cardiac differentiation of PSCs are mainly for adherent cells under 2D culture. Derivation of PSC-CMs in 3D, allowing for large-scale production of CMs via modulation of the Wnt/β-catenin signal pathway with defined chemicals and medium, may be desired for clinical translation. Furthermore, the technology of purification and maturation of the PSC-CMs may need further improvements to eliminate teratoma formation after in vivo implantation of the PSC-CMs for treating MI. In addition, in vitro derived PSC-CMs may have mechanical and electrical mismatch with the patient's cardiac tissue, which causes arrhythmia. This supports the use of PSC-derived cells committed to cardiac lineage without beating for implantation to treat MI. In this case, the PSC derived cells may utilize the mechanical, electrical, and chemical cues in the heart to further differentiate into mature/functional CMs in situ. Another major challenge facing stem cell therapy of MI is the low retention/survival of stem cells or their derivatives (e.g., PSC-CMs) in the heart for MI treatment after injection in vivo. This may be resolved by using biomaterials to engineer stem cells for reduced immunogenicity, immobilization of the cells in the heart, and increased integration with the host cardiac tissue. Biomaterials have also been applied in the derivation of CMs in vitro to increase the efficiency and maturation of differentiation. Collectively, a lot has been learned from the past failure of simply injecting intact stem cells or their derivatives in vivo for treating MI, and bioengineering stem cells with biomaterials is expected to be a valuable strategy for advancing stem cell therapy towards its widespread application for treating MI in the clinic.
心肌梗死（MI）是一种危及生命的疾病，由心肌细胞（CMs）不可逆死亡和心脏泵血功能减弱所致。在过去二十年中，基于干细胞的疗法已被用于研究MI的治疗，取得了有前景的成果。在本综述中，我们批判性地总结了该领域过去的工作，以阐明使用多能干细胞（PSCs）治疗MI的优缺点，这些多能干细胞包括胚胎干细胞（ESCs）和诱导多能干细胞（iPSCs）、成体干细胞以及心脏祖细胞。后者的主要优点是其产生细胞因子的能力，可调节免疫反应并控制愈合进程。然而，人类成体干细胞在体外或体内分化为功能性CMs的能力非常有限（如果不是“没有”能力的话）。相比之下，PSCs可以分化为功能性CMs，尽管PSCs向心脏分化的方案主要适用于二维培养下的贴壁细胞。通过使用特定化学物质和培养基调节Wnt/β-连环蛋白信号通路，在三维条件下衍生PSC-CMs，从而实现CMs的大规模生产，这可能是临床转化所需要的。此外，PSC-CMs的纯化和成熟技术可能需要进一步改进，以消除在体内植入PSC-CMs治疗MI后形成畸胎瘤的风险。另外，体外衍生的PSC-CMs可能与患者的心脏组织存在机械和电不匹配，从而导致心律失常。这支持使用致力于心脏谱系但不跳动的PSC衍生细胞进行植入以治疗MI。在这种情况下，PSC衍生细胞可以利用心脏中的机械、电和化学信号进一步在原位分化为成熟/功能性CMs。MI干细胞治疗面临的另一个主要挑战是，在体内注射后，用于MI治疗的干细胞或其衍生物（如PSC-CMs）在心脏中的保留/存活率较低。这可以通过使用生物材料对干细胞进行工程改造来解决，以降低免疫原性、将细胞固定在心脏中并增加与宿主心脏组织的整合。生物材料也已应用于体外CMs的衍生，以提高分化效率和成熟度。总的来说，从过去简单地在体内注射完整干细胞或其衍生物治疗MI的失败中我们学到了很多，用生物材料对干细胞进行生物工程有望成为一种有价值的策略，推动干细胞治疗在临床上广泛应用于治疗MI。
