Tolosa Laia, Pareja Eugenia, Gómez-Lechón Maria José
1 Unidad de Terapia Celular Hepática, Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe de Valencia, Valencia, Spain.2 Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe de Valencia, Valencia, Spain.3 Unidad de Cirugía Hepato-Bilio-Pancreática y Trasplante Hepático, Hospital Universitario y Politécnico La Fe de Valencia, Valencia, Spain.4 CIBERehd, FIS, Barcelona, Spain.
Transplantation. 2016 Dec;100(12):2548-2557. doi: 10.1097/TP.0000000000001426.
The worldwide shortage of donor livers for organ and hepatocyte transplantation has prompted the search for alternative therapies for intractable liver diseases. Cell-based therapy is envisaged as a useful therapeutic option to recover and stabilize the lost metabolic function for acute liver failure, end-stage and congenital liver diseases, or for those patients who are not considered eligible for organ transplantation. In recent years, research to identify alternative and reliable cell sources for transplantation that can be derived by reproducible methods has been encouraged. Human pluripotent stem cells (PSCs), which comprise both embryonic and induced PSCs, may offer many advantages as an alternative to hepatocytes for liver cell therapy. Their capacity for expansion, hepatic differentiation and self-renewal make them a promising source of unlimited numbers of hepatocyte-like cells for treating and repairing damaged livers. Immunogenicity and tumorigenicity of human PSCs remain the bottleneck for successful clinical application. However, recent advances made to develop disease-corrected hepatocyte-like cells from patients' human-induced PSCs by gene editing have opened up many potential gateways for the autologous treatment of hereditary liver diseases, which may likely reduce the risk of rejection and the need for lifelong immunosuppression. Well-defined methods to reduce the expression of oncogenic genes in induced PSCs, including protocols for their complete and safe hepatic differentiation, should be established to minimize the tumorigenicity of transplanted cells. On top of this, such new strategies are currently being rigorously tested and validated in preclinical studies before they can be safely transferred to clinical practice with patients.
全球范围内用于器官和肝细胞移植的供体肝脏短缺，促使人们寻找治疗顽固性肝病的替代疗法。基于细胞的疗法被视为一种有用的治疗选择，可恢复和稳定急性肝衰竭、终末期和先天性肝病患者丧失的代谢功能，或用于那些被认为不符合器官移植条件的患者。近年来，人们鼓励开展研究，以确定可通过可重复方法获得的替代且可靠的移植细胞来源。人类多能干细胞（PSCs），包括胚胎干细胞和诱导多能干细胞，作为肝细胞治疗的替代物可能具有许多优势。它们的扩增、肝分化和自我更新能力使其成为治疗和修复受损肝脏的无限数量肝样细胞的有希望的来源。人类PSCs的免疫原性和致瘤性仍然是其成功临床应用的瓶颈。然而，最近通过基因编辑从患者的人类诱导多能干细胞中开发疾病校正肝样细胞的进展，为遗传性肝病的自体治疗开辟了许多潜在途径，这可能会降低排斥反应的风险和终身免疫抑制的需求。应建立明确的方法来降低诱导多能干细胞中致癌基因的表达，包括其完全和安全的肝分化方案，以尽量减少移植细胞的致瘤性。除此之外，此类新策略目前正在临床前研究中进行严格测试和验证，然后才能安全地应用于患者的临床实践。
