Stoltz J-F, Zhang L, Ye J S, De Isla N
CNRS, UMR 7365, Biopole, Faculté de Médecine, 54500 Vandoeuvre-Lès-Nancy, France.
CNRS, GDRI 0851, France-Chine « Stem cells and Regenerative medicine », Faculté de Médecine, 54511 Vandoeuvre-Lès-Nancy, France.
Biomed Mater Eng. 2017;28(s1):S121-S127. doi: 10.3233/BME-171633.
The relevance of research on reconstructed organs is justified by the lack of organs available for transplant and the growing needs for the ageing population. The development of a reconstructed organ involves two parallel complementary steps: de-cellularization of the organ with the need to maintain the structural integrity of the extracellular matrix and vascular network and re-cellularization of the scaffold with stem cells or resident cells.Whole organ engineering for liver, heart, lung or kidneys, is particularly difficult because of the structural complexity of organs and heterogeneity of cells. Rodent, porcine and rhesus monkey organs have been de-cellularized to obtain a scaffold with preserved extracellular matrix and vascular network. As concern the cells for re-cellularization, embryonic, foetal, adult, progenitor stem cells and also iPS have been proposed.Heart construction could be an alternative option for the treatment of cardiac insufficiency. It is based on the use of an extra-cellular matrix coming from an animal's heart and seeded with cells likely to reconstruct a normal cardiac function. Though de-cellularization techniques now seem controlled, the issues posed by the selection of cells capable of generating the various components of cardiac tissue are not settled yet. In addition, the recolonisation of the matrix does not only depend on the phenotype of cells that are used, but it is also impacted by the nature of biochemical signals emitted.Recent researches have shown that it is possible to use decellularized whole liver treated by detergents as scaffold, which keeps the entire network of blood vessels and the integrated extracellular matrix (ECM). Beside of decellularized whole organ scaffold seeding cells selected to repopulate a decellularized liver scaffold are critical for the function of the bioengineered liver. At present, potential cell sources are hepatocyte, and mesenchymal stem cells.Pulmonary regeneration using engineering approaches is complex. In fact, several types of local progenitor cells that contribute to cell repair have been described at different levels of the respiratory tract. Moving towards the alveoles, one finds bronchioalveolar stem cells as well as epithelial cells and pneumocytes. A promising option to increase the donor organ pool is to use allogeneic or xenogeneic decellularized lungs as a scaffold to engineer functional lung tissue ex vivo.The kidney is certainly one of the most difficult organs to reconstruct due to its complex nature and the heterogeneous nature of the cells. There is relatively little research on auto-construction, and experiments have been performed on rats, pigs and monkeys.Nevertheless, before these therapeutic approaches can be applied in clinical practice, many researches are necessary to understand and in particular the behaviour of cells on the decellularized organs as well as the mechanisms of their interaction with the microenvironment. Current knowledges allow optimism for the future but definitive answers can only be given after long term animal studies and controlled clinical studies.
由于可用于移植的器官短缺以及老龄化人口需求的不断增长,对重建器官的研究具有重要意义。重建器官的发展涉及两个并行的互补步骤:使器官去细胞化,同时需要保持细胞外基质和血管网络的结构完整性;用干细胞或驻留细胞使支架重新细胞化。由于器官的结构复杂性和细胞的异质性,肝脏、心脏、肺或肾脏的全器官工程尤其困难。啮齿动物、猪和恒河猴的器官已被去细胞化,以获得保留细胞外基质和血管网络的支架。关于用于重新细胞化的细胞,有人提出了胚胎、胎儿、成体、祖干细胞以及诱导多能干细胞。心脏构建可能是治疗心脏功能不全的一种替代选择。它基于使用来自动物心脏的细胞外基质,并接种可能重建正常心脏功能的细胞。尽管现在去细胞化技术似乎已得到控制,但选择能够生成心脏组织各种成分的细胞所带来的问题尚未解决。此外,基质的重新定植不仅取决于所用细胞的表型,还受到所发出的生化信号性质的影响。最近的研究表明,可以使用经洗涤剂处理的去细胞化全肝作为支架,该支架保留了整个血管网络和完整的细胞外基质(ECM)。除了去细胞化全器官支架外,选择接种到去细胞化肝脏支架上的细胞对于生物工程肝脏的功能至关重要。目前,潜在的细胞来源是肝细胞和间充质干细胞。使用工程方法进行肺再生很复杂。事实上,在呼吸道的不同层面已经描述了几种有助于细胞修复的局部祖细胞类型。朝着肺泡方向,人们发现了支气管肺泡干细胞以及上皮细胞和肺细胞。增加供体器官库的一个有前景的选择是使用同种异体或异种去细胞化肺作为支架,在体外构建功能性肺组织。由于肾脏的复杂性质和细胞的异质性,它肯定是最难重建的器官之一。关于自体构建的研究相对较少,并且已经在大鼠、猪和猴子身上进行了实验。然而,在这些治疗方法能够应用于临床实践之前,需要进行许多研究,特别是要了解细胞在去细胞化器官上的行为以及它们与微环境相互作用的机制。目前的知识让人们对未来感到乐观,但只有经过长期的动物研究和对照临床研究才能给出明确的答案。