Laboratory of Neuronal Plasticity and Neurorepair, Institute for Neuroscience of Castile and Leon (INCyL), University of Salamanca, Salamanca, Spain.
Institute of Biomedical Research of Salamanca, IBSAL, Salamanca, Spain.
J Tissue Eng Regen Med. 2019 Sep;13(9):1702-1711. doi: 10.1002/term.2925. Epub 2019 Jul 25.
Cell therapy has been proven to be a promising treatment for fighting neurodegenerative diseases. As neuronal replacement presents undeniable complications, the neuroprotection of live neurons arises as the most suitable therapeutic approach. Accordingly, the earlier the diagnosis and treatment, the better the prognosis. However, these diseases are commonly diagnosed when symptoms have already progressed towards an irreversible degenerative stage. This problem is especially dramatic when neurodegeneration is aggressive and rapidly progresses. One of the most interesting approaches for neuroprotection is the fusion between healthy bone marrow-derived cells and neurons, as the former can provide the latter with regular/protective genes without harming brain parenchyma. So far, this phenomenon has only been identified in Purkinje cells, whose death is the cause of different diseases like cerebellar ataxias. Here we have employed a model of aggressive cerebellar neurodegeneration, the Purkinje Cell Degeneration mouse, to optimize a cell therapy based on bone marrow-derived cell and cell fusion. Our findings show that the substitution of bone marrow in diseased animals by healthy bone marrow, even prior to the onset of neurodegeneration, is not fast enough to stop neuronal loss in time. Conversely, avoiding bone marrow replacement and ensuring a regular supply of healthy cells through continuous, daily transplants, the neurodegenerative milieu of PCD is enough to attract those transplanted elements. Furthermore, in the most affected cerebellar regions, more than a half of surviving neurons undergo a process of cell fusion. Therefore, this method deserves consideration as a means to impede neuronal cell death.
细胞治疗已被证明是治疗神经退行性疾病的一种很有前途的方法。由于神经元替代存在不可否认的并发症，因此活神经元的神经保护成为最适合的治疗方法。因此，越早诊断和治疗，预后越好。然而，这些疾病通常在症状已经发展到不可逆转的退行阶段时才被诊断出来。当神经退行性变具有侵袭性且快速进展时，这个问题尤其严重。神经保护最有趣的方法之一是健康骨髓源性细胞与神经元融合，因为前者可以向后者提供正常/保护性基因，而不会损害脑实质。到目前为止，这种现象仅在浦肯野细胞中被发现，浦肯野细胞的死亡是不同疾病（如小脑共济失调）的原因。在这里，我们采用了一种侵袭性小脑神经退行性变模型，即浦肯野细胞退化小鼠，以优化基于骨髓源性细胞和细胞融合的细胞治疗。我们的研究结果表明，在疾病动物中用健康骨髓替代骨髓，即使在神经退行性变发生之前，也不足以及时阻止神经元丢失。相反，通过持续、每日移植来避免骨髓替代并确保健康细胞的正常供应，PCD 的神经退行性环境足以吸引那些移植的细胞。此外，在受影响最严重的小脑区域，超过一半的存活神经元经历细胞融合过程。因此，这种方法值得考虑作为阻止神经元细胞死亡的一种手段。
