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Возможность задания различных нейральных подтипов в пробирке имеет очевидные клинические и экспериментальные пути развития для нервной де- и регенерации. DA-нейроны были одними из первых нейронов подтипа, непосредственно индуцированной из мыши, так и фибробластов человека в 2011 году (Caiazzo et al. 2011; Pfisterer et al. 2011). В обоих исследованиях активно наблюдаются пики, TH-положительные, индуцированные дофаминергические нейроны (IDA нейронные клетки) были охарактеризованы, хотя пулы различных факторов были использованы для достижения этих результатов, и только клетки, индуцированные экспрессией Ascl1, Nurr1, и Lmx1a продемонстрировали высвобождение допамина (Caiazzo et al. 2011). Появление этих факторов привело к IDA нервных клеток, полученных из двух здоровых пациентов и пациентов с PD. Такой подход имеет далеко идущие последствия для Паркинсона, связанного с дегенерацией нейронов DA, так как эти перепрограммированные клетки предположительно могут быть использованы для замены тех, которые были потеряны.
Альтернативные усилия стремились перепросматривать специфическую среднемозговую идентичность DA-нейронов, потерянных в PD, с выводами, что еще один пул факторов способен вызывать дофаминергические нервные клетки. Тем не менее, панель DA и пан-нейральных генов показали уровни экспрессии в клетках IDA, не оправдали ожиданий по сравнению с найденными в эмбриональных или взрослых среднемозговых нейронах DA, хотя эти клетки IDA способны частично восстанавливать функции дофамина при трансплантации в мышей с PD (Kim et al. 2011).
Помимо возможности вывести нейронные клетки DA с помощью стратегий перепрограммирования, с соответствующими последствиями для PD, усилия также сосредоточены на расстройствах, влияющих на спинальные двигательные нейроны, такие как ALS (болезнь Лу Герига) или SMA. Недавние исследования показали, что моторные нейроны могут быть непосредственно индуцированны из фибробластов [Индуцированные двигательных нейронов (iMN) клеток], используя принудительную экспрессию пула факторов транскрипции, который включал вышеупомянутый BAM коктейль факторов транскрипции наряду с моторными нейронами специфических факторов (Son et al 2011). Подобно эмбриональным и ESC-полученных двигательных нейронов, эти клетки iMN были избирательно чувствительны к токсичности, вызванной мутантными глиальными клетками от модели мыши БАС в совместной культуре, демонстрируя свою полезность как в качестве фенокопии моторных нейронов при болезнях, таких как SMA или ALS, а также для изучения вклада клеточных автономных в дегенерацию (Di Giorgio et al. 2007; Nagai et al. 2007). Знаковые проверки и подтверждение принципа действия исследования, несомненно, вдохновит исследователей и клиницистов, поскольку они стремятся развивать нейронные регенерационные стратегии для широкого спектра дегенеративных расстройств.
5.5 Будущие последствия и вопросы о перепрограммировании в отношении регенерации
The many studies discussed in this chapter made significant discoveries that markedly changed, and will continue to shape, our current understanding of regeneration. As the field of reprogramming has exploded in the last decades, an increasingly apparent need for standardization exists. Currently variations in induction methods, nomenclature, efficiency calculations, quantification methods for the extent of reprogramming, and the methods used to demonstrate functionality of derived cells currently make direct comparisons difficult. Marius Wernig’s group, who was first to develop direct reprogramming for iN cells in 2010, recently proposed a panel of criteria to be used to define iN cells with various degrees of reprogramming (Yang et al. 2011). The increasingly stringent criteria are also roughly the order of appearance of aforementioned neuronal properties in both reprogrammed iN cells and neurons during development. Broadly, they include the stepwise appearance of neuronal traits from (1) common morphological features, to (2) unique membrane characteristics, and finally (3) output function. For instance, a characteristic neuronal morphology is the first measureable changed observed, using the specific criteria of complex dendritic arborization, while synaptic plasticity, as demonstrated by short-term facilitation/depression, is the final property to appear. Between these two endpoints exist iN cells with varying degrees of reprogramming, and the authors have offered quantifiable criteria to define the extent of this reprogramming. They also point out the subtle conceptual difference between ‘‘partially reprogrammed iN cells’’ and ‘‘immature iN cells,’’ though until mechanisms underlying this process are further elucidated, distinguishing between the two is difficult.
Furthermore, issues of safety and efficiency continue to be a concern. As discussed previously, many recent studies have developed tools aimed at avoiding/ removing genome integration events caused by the retro- or lentiviral delivery of genes. This field is advancing rapidly and the affordability of these technologies will continue to increase, as will their efficiencies. The current four-factor lentiviral induction method used for the human system only had an overall efficiency of 2–4 % (Pang et al. 2011), 10-fold lower than the three-factor system used for mouse (Vierbuchen et al. 2010), though direct somatic cell reprogramming methods have generally so far seen higher conversion efficiencies than those observed in iPSC line establishment. As methods are optimized and new genes and compounds are tested, these numbers are expected to only further increase.
As methods for both indirect and direct reprogramming continue to improve, and the mechanisms for each are further delineated, many differences between the two may shrink in significance. However, one major difference between indirect and direct reprogramming is the lack of required cell proliferation in direct reprogramming. This absence could prove to be a detriment for regenerative applications of direct reprogramming, as large numbers of cells are required for transplantation in cellular replacement strategies, and the ability of reprogrammed cells to proliferate in vitro may prove beneficial, or even necessary. As direct reprogramming is currently a much less arduous process than that used to first establish iPSCs and then redifferentiate them, efforts have also focused on directly reprogramming somatic cells into lineage-specific stem cells, such as neural stem cells, in one step. It was indeed demonstrated that functional, bipotent, induced neural progenitor cells (iNPCs) could be derived from mouse fibroblasts by first inducing the overexpression of a set of the pluripotency factors used to establish iPSCs (Oct4, Kl4, Sox2, and c-myc) for 3–6 days, and then allowing the cells to expand in neural reprogramming media supplemented with FGF2, EGF, and FGF4 to support NPCs (Kim et al. 2011a). These iNPCs spontaneously differentiated into multiple neuronal cell types, as well as astrocytes, demonstrating at least a bipotent progenitor. Although these cells did not expand well in culture, they represent another possible unique application of reprogramming for regenerative purposes. As the field of reprogramming is a relatively young one, the current explosion in publications on this topic will continue to deepen our understanding of this dynamic and responsive process. The applicability of those discoveries, to neural regeneration and other biological processes, seems only limited by our imaginations.
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