Brain repair for Parkinson’s disease:is the answer in the matrix?

Two hundred years after James Parkinson fi rst described the cardinal motor symptoms of the disorder that would later bear his name, there is still an irrefutable need for a therapy that targets the underlying pathophysiology of the disease and not solely its symptoms. Parkinson’s disease (PD) is classically characterised by Lewy body formation and a relatively selective degeneration of nigrostriatal dopaminergic neurons (Schapira and Jenner, 2011). The loss of dopaminergic neurons from the substantia nigra pars compacta causes a consequential depletion of the neurotransmitter dopamine from the striatum, and it is this loss that causes the motor symptoms experienced by patients.To date, all treatments for this condition are symptomatic in that they simply endeavour to correct the neurochemical and/or electrical anomalies caused by striatal dopaminergic deafferentation in an attempt to improve motor function (LeWitt and Fahn, 2016). While such symptomatic approaches show extraordinary efficacy in the early years after initiating treatment, the underlying disease pathology continues to progress, and eventually their efficacy subsides. In view of this, there remains an urgent need for an alternative treatment approach that is capable of protecting or repairing the brain in order to provide a more sustained bene fi t to patients.

Brain repair for PD:Brain repair for PD has developed from a relatively simple conceptual framework - if a primary pathological hallmark of the disease is the degeneration and death of dopaminergic neurons, then it should be possible to replace these neurons with healthy, viable cells. Over the last 30 years, cell replacement therapy for PD has focused on the transplantation of primary dopaminergic neurons sourced from the ventral mesencephalon of fetal donor tissue. A plethora of experimental studies from rodents to non-human primates have illustrated the ability of these cells to survive, integrate with the host system, release dopamine and restore motor function;results that have since translated to clinical trials in PD patients(Barker et al., 2015). However, despite the potential of brain repair for PD, the use of human fetal tissue, obtained from elective abortions,raises many ethical and logistical concerns, which are exacerbated by the extremely poor survival of these cells in the brain post-transplantation (Sortwell et al., 2000). With a survival rate of only 5—10% of implanted cells, there is a requirement for as many as 12 fetal donors per patient which is clearly an impediment to the more widespread roll-out of this approach to patients (Barker et al., 2013). Several factors, occurring at various points of the transplantation process, are thought to contribute to the poor survival of the implanted fetal cells.These include 1) detachment from the extracellular matrix during tissue dissection, 2) growth factor deprivation upon transplantation into the adult striatum, and 3) the host brain’s neuroinflammatory response to the implanted cells (Moriarty et al., 2017).

Biomaterials improve brain repair in PD models:We have recently embarked on a series of studies to determine if the conceptual bene fi ts of biomaterial hydrogels can be realised in experimental studies (Hoban et al., 2013; Newland et al., 2013; Samal et al., 2015; Moriarty et al.,2017). In the fi rst instance, we found a dramatic reduction in the host’s immune response to transplanted cells (mesenchymal stem cells or primary dopaminergic neurons) when these are injected into the brain in anin situgelling collagen hydrogel (Hoban et al., 2013; Moriarty et al.,2017). This was manifest through a signi fi cant reduction in the recruitment and proliferation of both microglia and astrocytes at the transplantation site. Given that intracerebral transplantation of these cells usually stimulates a substantial host immune response, the collagen hydrogel was clearly capable of shielding the grafted cells by forming a physical barrier between the cells and the host brain’s immune cells.However, despite the signi fi cant reduction in gliosis at the transplant site, this was not sufficient to improve the survival of either mesenchymal stem cell or primary dopaminergic transplants. We hypothesised that this was due to the lack of trophic support immediately upon transplantation, as this is the critical period were the vast majority of cell death is known to occur. Therefore, we then sought to determine if the collagen hydrogel was capable of providing a growth factor reservoir in the brain by functionalising the gels with the dopaminergic neurotrophin, glial-derived neurotrophic factor (GDNF). Injection of GDNF within the hydrogel resulted in a signi fi cantly enhanced acute retention of the trophic factor in the brain when compared with a bolus injection of GDNF (Moriarty et al., 2017). We then hypothesised that the GDNF-functionalised hydrogel could provide implanted cells with the localised trophic support required during the critical period immediately post-transplantation which is lacking during the conventional delivery of ventral mesencephalic tissue alone. Strikingly, when we transplanted primary dopaminergic neurons in the GDNF-functionalisedin situgelling collagen hydrogel, we found that cell survival was significantly and substantially (5-fold) enhanced, and that this was associated with a greater extent of striatal reinnervation from the grafted cells which translated to a greater level of functional recovery(Figure 2, Moriarty et al., 2017). Taken together, these data indicate that collagen hydrogels can indeed target multiple points of cell death by providing cells with a supportive environment throughout transplantation that is rich in trophic support and capable of guarding the cells from the hostile host environment.

Consistent with these findings, other research groups have also recently reported the benefits of biomaterial application to cell replacement therapies in PD models. Wang et al. (2016) demonstrated the enhanced survival and re-innervation of transplanted fetal ventral mesencephalon grafts through their encapsulation in a GDNF containing composite scaffold consisting of a xyloglucan hydrogel and electrospun short nano fi bers. An interesting addition to this scaffold was the tethering of GDNF to short nano fi bers, alongside the presence of soluble GDNF throughout the hydrogel, thus providing longterm GDNF delivery at the graft site and sustained release from the hydrogel. Moreover, since the tethering of GDNF to the short nanofi bers alone did not result in improved cell survival or re-innervation,this highlights the importance of GDNF release from the graft core to the surrounding striatum, where it can guide and support neurite outgrowth. Adil et al. (2017) have also recently demonstrated that a hyaluronic acid hydrogel can enhance the survival of, and neurite outgrowth from, encapsulated human embryonic stem cell-derived dopaminergic neurons. This hydrogel was additionally functionalised with extracellular membrane derived ligands, RGD and heparin, in an effort to assist cell attachment and trophic factor binding, respectively. Moreover, this study demonstrated the ability of the functionalised hydrogel to improve the efficacy of dopaminergic neuronal differentiation, with a higher fraction of dopaminergic cells obtainedin vitro,and an increase in the number of surviving cells during enzymatic cell harvest, a step that is thought to be a major contributing factor to pre-transplantation cell death in stem cell therapies. Encouragingly,this further demonstrates the potential of biomaterial applications in future stem cell-based cell replacement therapies.

Figure 1 Therapeutic concept of biomaterials for brain repair in Parkinson’s disease.

Figure 2 Glial-derived neurotrophic factor(GDNF)-functionalized collagen hydrogels improve brain repair in Parkinsonian rats.

The future of biomaterials for brain repair for PD:It is clear that evidence is mounting that supports the potential of biomaterial scaffolds to enhance brain repair for PD. As cell therapies for PD and other neurodegenerative disorders propel towards the clinic, simultaneously, the area of biomaterial science is also making monumental progress; and the question remains: “is the answer in the matrix?”While further work must be carried out to determine the optimal material for dopaminergic cell replacement therapies, it is indisputable that great potential lies within biomaterial scaffolds and their application to neuroregenerative therapies.

Our research in this fi eld is supported by the European Union Horizon 2020 Programme (H2020-MSCA-ITN-2015) under the Marie Sklodowska-Curie Innovative Training Networks and Grant Agreement No. 676408, Science Foundation Ireland (11/RFP/NES/3183),and through a postgraduate scholarship from the Irish Research Council to Niamh Moriarty.

Niamh Moriarty, Eilís Dowd＊

Pharmacology & Therapeutics and Galway Neuroscience Centre,National University of Ireland, Galway, Ireland

＊Correspondence to:Eilís Dowd, BSc, Ph.D.,eilis.dowd@nuigalway.ie.

orcid:0000-0002-2668-539X (Eilís Dowd)

Accepted:2018-05-04

1998年广州日报印务中心投资10亿元，引进了4条高速印报生产线，可达每小时300万对开张的产能。此后为适应报纸发行数量和版面数量不断增加，又相继进行了4次设备扩展，最终达到6条高速印报生产线，总计654万对开张/小时的产能。即使在世界范围内，当时这些生产线的配置也是相当超前的，从纸墨输送-报纸印刷-传送打包-装车发运，报纸印刷全流程实现了物料传送自动化。我们现在看到的生产系统架构都是20年前就已做出的。即使在今天，也仍是国内规模最大、配置最完善的报纸印刷生产系统之一。

doi:10.4103/1673-5374.235027

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Open access statement:This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

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Reviewer:Sagar Gaikwad, Indian Institute of Advanced Research, India.

Comments to authors:The perspective article highlights the potential implications of biomaterials for enhancing neuronal repair. In particular, authors discuss the potential use of GDNF-loaded collagen hydrogel scaffolds for thetransplantation of primary dopaminergic neurons to the to improve the outcome of reparative cell therapies for PD. The article is very interesting, and has its merit and represents a valuable contribution to the literature.