de Vasconcelos Pedro, Lacerda João F
Serviço de Hematologia e Transplantação de Medula, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal.
JLacerda Lab, Hematology and Transplantation Immunology, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
Front Cell Neurosci. 2022 May 26;16:895511. doi: 10.3389/fncel.2022.895511. eCollection 2022.
Hematopoietic stem cells have been investigated and applied for the treatment of certain neurological disorders for a long time. Currently, their therapeutic potential is harnessed in autologous and allogeneic hematopoietic stem cell transplantation (HSCT). Autologous HSCT is helpful in immune-mediated neurological diseases such as Multiple Sclerosis. However, clinical benefits derive more from the immunosuppressive conditioning regimen than the interaction between stem cells and the nervous system. Mainly used for hematologic malignancies, allogeneic HSCT explores the therapeutic potential of donor-derived hematopoietic stem cells. In the neurological setting, it has proven to be most valuable in Inborn Errors of Metabolism, a large spectrum of multisystem disorders characterized by congenital deficiencies in enzymes involved in metabolic pathways. Inborn Errors of Metabolism such as X-linked Adrenoleukodystrophy present with brain accumulation of enzymatic substrates that result in progressive inflammatory demyelination. Allogeneic HSCT can halt ongoing inflammatory neural destruction by replacing hematopoietic-originated microglia with donor-derived myeloid precursors. Microglia, the only neural cells successfully transplanted thus far, are the most valuable source of central nervous system metabolic correction and play a significant role in the crosstalk between the brain and hematopoietic stem cells. After transplantation, engrafted donor-derived myeloid cells modulate the neural microenvironment by recapitulating microglial functions and enhancing repair mechanisms such as remyelination. In some disorders, additional benefits result from the donor hematopoietic stem cell secretome that cross-corrects neighboring neural cells mannose-6-phosphatase paracrine pathways. The limitations of allogeneic HSCT in this setting relate to the slow turnover of microglia and complications such as graft-vs.-host disease. These restraints have accelerated the development of hematopoietic stem cell gene therapy, where autologous hematopoietic stem cells are collected, manipulated to overexpress the missing enzyme, and infused back into the patient. With this cellular drug vehicle strategy, the brain is populated by improved cells and exposed to supraphysiological levels of the flawed protein, resulting in metabolic correction. This review focuses on the mechanisms of brain repair resulting from HSCT and gene therapy in Inborn Errors of Metabolism. A brief mention will also be made on immune-mediated nervous system diseases that are treated with this approach.
造血干细胞已被研究并应用于某些神经系统疾病的治疗很长时间了。目前，它们的治疗潜力在自体和异体造血干细胞移植（HSCT）中得到了利用。自体HSCT对免疫介导的神经系统疾病如多发性硬化症有帮助。然而，临床益处更多地来自免疫抑制预处理方案，而非干细胞与神经系统之间的相互作用。异体HSCT主要用于血液系统恶性肿瘤，它探索了供体来源的造血干细胞的治疗潜力。在神经系统疾病中，它已被证明在先天性代谢缺陷疾病中最有价值，这是一大类多系统疾病，其特征是参与代谢途径的酶存在先天性缺陷。诸如X连锁肾上腺脑白质营养不良等先天性代谢缺陷疾病会出现酶底物在脑内蓄积，导致进行性炎症性脱髓鞘。异体HSCT可以通过用供体来源的髓系前体细胞替代造血起源的小胶质细胞来阻止正在进行的炎症性神经破坏。小胶质细胞是迄今为止唯一成功移植的神经细胞，是中枢神经系统代谢纠正的最有价值来源，并且在脑与造血干细胞之间的相互作用中发挥重要作用。移植后，植入的供体来源的髓系细胞通过重现小胶质细胞功能并增强诸如髓鞘再生等修复机制来调节神经微环境。在某些疾病中，额外的益处来自供体造血干细胞分泌组，它通过旁分泌途径交叉纠正邻近的神经细胞的甘露糖-6-磷酸酶。在这种情况下，异体HSCT的局限性与小胶质细胞更新缓慢以及移植物抗宿主病等并发症有关。这些限制加速了造血干细胞基因治疗的发展，即收集自体造血干细胞，进行操作使其过表达缺失的酶，然后再回输到患者体内。通过这种细胞药物载体策略，大脑中会有改良的细胞，并暴露于超生理水平的缺陷蛋白中，从而实现代谢纠正。本综述重点关注先天性代谢缺陷疾病中HSCT和基因治疗导致脑修复的机制。还将简要提及用这种方法治疗的免疫介导的神经系统疾病。
