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 Table of Contents  
Year : 2020  |  Volume : 15  |  Issue : 7  |  Page : 1173-1178

Glial cells in intracerebral transplantation for Parkinson’s disease

Institute of Anatomy, University of Bern, Baltzerstrasse 2, 3012 Bern, Switzerland

Date of Submission31-Jul-2019
Date of Decision02-Aug-2019
Date of Acceptance02-Sep-2019
Date of Web Publication09-Jan-2020

Correspondence Address:
Nikola Tomov
Institute of Anatomy, University of Bern, Baltzerstrasse 2, 3012 Bern
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1673-5374.270296

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In the last few decades, intracerebral transplantation has grown from a dubious neuroscientific topic to a plausible modality for treatment of neurological disorders. The possibility for cell replacement opens a new field of perspectives in the therapy of neurodegenerative disorders, ischemia, and neurotrauma, with the most lessons learned from intracerebral transplantation in Parkinson’s disease. Multiple animal studies and a few small-scale clinical trials have proven the concept of intracerebral grafting, but still have to provide a uniform and highly efficient approach to the procedure, suitable for clinical application. The success of intracerebral transplantation is highly dependent on the integration of the grafted cells with the host brain. In this process, glial cells are clearly more than passive bystanders. They provide transplanted cells with mechanical support, trophics, mediate synapse formation, and participate in graft vascularization. At the same time, glial cells mediate scarring, graft rejection, and neuroinflammation, which can be detrimental. We can use this information to try to understand the mechanisms behind the glial reaction to intracerebral transplantation. Recognizing and utilizing glial reactivity can move translational research forward and provide an insight not only to post-transplantation events but also to mechanisms of neuronal death and degeneration. Knowledge about glial reactivity to transplanted cells could also be a key for optimization of transplantation protocols, which ultimately should contribute to greater patient benefit.

Keywords: astroglia; dopaminergic; glial scarring; microglia; neuroinflammation; Parkinson’s disease; transplantation

How to cite this article:
Tomov N. Glial cells in intracerebral transplantation for Parkinson’s disease. Neural Regen Res 2020;15:1173-8

How to cite this URL:
Tomov N. Glial cells in intracerebral transplantation for Parkinson’s disease. Neural Regen Res [serial online] 2020 [cited 2021 Aug 5];15:1173-8. Available from: http://www.nrronline.org/text.asp?2020/15/7/1173/270296

  Introduction Top

The concept of neural transplantation is not new. The very first report of transplantation of neural tissue to the central nervous system (CNS) dates back to the end of the 19th century (Thompson, 1890) and does include an account of what is surely a glial reaction. The “organized connective tissue” on the interface between grafted tissue and host brain was, most likely, fibrin deposit, combined with some glial scar tissue. It was firstly recognized and described as a glial layer some 15 years later (Saltykow, 1905), however, without any comments regarding its origin and functional importance. In the years to come, only occasional reports of intracerebral transplantation have been published, with scarce descriptions of glia, such as the observation of glial cell proliferation in grafted tissue by Le Gros Clark (1940).

Gopal Das (Björklund, 1999) has given the first modern and scientifically sound description of the events following intracerebral transplantation. By demonstrating cell migration from the graft towards the host brain (Das and Altman, 1971, 1972; Das et al., 1973), it was shown that the graft-host interface is not a static barrier, but rather a dynamic structure and site of intensive cell-cell interaction. Shortly thereafter, a functional integration of transplanted neural cells and host brain (Björklund and Stenevi, 1979; Perlow et al., 1979) was demonstrated. An account of glial reaction has been provided in those seminal works - a glial layer, mediating graft adherence to the host brain tissue has been described (Björklund and Stenevi, 1979). Another observation of interplay between grafted cells and host glia has been made by Perlow et al. (1979), noting growth of ependymal cells parallel to axons, growing out of the graft. After those seminal reports, neural transplantation was seen as a possible modality for cell replacement in neurodegenerative disease, which has led to an expansion of experiments in different settings, utilizing different protocols. However, the focus of those studies has almost exclusively been on the neuronal interactions, while glial cells have been more modestly commented.

Probably the most abundant body of information regarding intracerebral transplantation exists in the context of dopaminergic grafting in Parkinson’s disease (PD), gathered both in animal models, as well as in some clinical trials. Despite the concept of replacing a certain degenerated cell population (in that case dopaminergic neurons) with the intent of reversing the deficit provoked by their degeneration is very straightforward, the practical results are often not so consistent. What is known both from animal studies as well as from the limited clinical experience is that intracerebral transplantation does not always work as intended. Although the procedure is generally considered safe, its efficacy is variable, and side effects are often observed (Wenker and Pitossi, 2019). Multiple factors, which may influence the outcome, have been discussed, including the choice of cells for transplantation, the preparation of the material for grafting, the procedure itself, and the condition of the host brain (Collier et al., 2019). The role of glia following grafting has been marginally discussed, mostly in the context of immune reaction following grafting. The present review aims to draw attention towards the somewhat disregarded role of glial cells in intracerebral transplantation. This can attempt to elucidate the complex post-transplantational processes and give a perspective towards optimization of transplantation protocols.

  Search Strategy and Selection Criteria Top

The articles cited in the present review were retrieved from a search in the NCBI PubMed database using “intracerebral transplantation” as keyword. Results were manually screened so relevant works containing information about astroglial and microglial reaction to transplantation were included.

  Astrocytes and Transplantation Top

Any injury to the CNS leads to a gliotic reaction. Astrocytes around the lesion act to seal off the brain from the tissue defect. They vigorously proliferate and produce many interwoven processes, which come in contact with one another. In the uninjured CNS, astroglial cells normally produce a plentiful extracellular matrix. Upon activation by trauma, some of its components get specifically upregulated in traumatic areas only. Some of those components, such as tenascin, are inhibitory for axon growth, while others such as laminin are permissive. Furthermore, the astrocytes modulate their environment, by secreting a wide spectrum of molecules, and many of them are also neurotrophic (Barker et al., 1996).

In general, reactive astrogliosis has been schematically categorized into isomorphic (neuroprotective) and anisomorphic (scar forming). Both types may appear simultaneously at different sites following a single lesion (Ferrer, 2017), and grafting to the CNS is one of those instances. Intracerebral transplantation causes an intensive astroglial activation, which is caused by both the inevitable trauma caused by the surgery (anisomorphic), as well as the interaction between grafted cells and host brain (isomorphic).

When the neural tissue is injured, astrocytes principally act to seal off the damaged territories. By producing a glial scar, they isolate lesioned areas of the CNS, while simultaneously supporting the regeneration. Reactive astrogliosis is an extremely heterogeneous process, which can be caused by different stimuli, is mediated by different factors, has distinct functions, and leads to a multitude of, sometimes even opposite, effects (Ferrer, 2017). Extensive scarring is known to inhibit axonal growth, imposing a major barrier to regeneration. At the same time, astrocytes provide crucial trophic support at the injury site (Rolls et al., 2009). In grafting, the transplanted neural cells are challenged twofold. For successful transplantation, firstly, they have to survive the severe conditions surrounding the grafting itself, and secondly, they have to achieve integration with the host brain, and in these tasks, they encounter the two faces of the astroglial scar.

The relationship between the degree of trauma during transplantation and the percentage of transplanted cells, which integrate with the host brain, is well studied. Using a more traumatic approach leads to stronger reactive astrogliosis and to poorer survival of transplanted neurons (Nikkhah et al., 1994). In this situation, it is not clear if the correlation between the extent of astrogliosis and the number of surviving transplanted cells is directly casual. Vast glial scarring, however, could be considered rather detrimental, being a difficultly penetrable barrier for neurites, interfering with the ultimate goal of reinnervation (Silver and Miller, 2004). This has led to refining of surgical approaches; the way the cells are delivered to the host brain is still subject of ongoing research (Barker et al., 2019). Despite attempts to reduce trauma, it should be noted that the tissue disruption caused by the surgical approach is an unevitable event, since the blood-brain barrier is breached at the moment of the insertion of even the most elegant grafting instrument. Therefore, trauma-induced astroglial activation will always be present following transplantation.

However, what is observable as extensive astroglial recruitment around grafts, is not per se a glial scar, and is not automatically deleterious. A recent study (Tomov et al., 2018) shows that grafted cells apparently actively induce astrogliosis surrounding the graft. This astrogliosis can be categorized under the already discussed isomorphic type. Evidence from this study suggests that astrocytes produce a glial scaffold for the grafted dopaminergic cells. By orienting their processes parallel to the axons growing out from the transplanted neurons (Isacson et al., 1995, Mendez et al., 2005), astroglia of the host brain actually actively aid the reinnervation of the dopamine-depleted striatum. Furthermore, it is known that following grafting, some afferent projections from the host brain can also reach the transplant (Petit et al., 2001). In both cases, the astroglial envelope around the graft is a penetrable barrier for neurites (Li et al., 2012), among others because it contains less extracellular matrix, which is preconditioned by the presence of transplanted cells (Barker et al., 1996).

Consistent with the idea of the tripartite synapse (i.e., presynapse, postsynapse, and astrocyte), the astroglia of the host striatum plays a crucial role in the synaptic integration of the grafted cells. It is widely known that astrocytes associated with synapses exchange information with neurons, with implications for sustaining synaptic strength. In the context of PD, data shows that there is a significant increase of astrocytic presence in striatal tripartite synapses in the parkinsonian brain (Villaba and Smith, 2011). This further highlights the role of astrocytes in restoring the neuronal circuitry following grafting and gives a good explanation of the observed intensive astroglial recruitment around grafts.

Another beneficial aspect of astroglial activation following transplantation is providing trophics for the grafted tissue. The astrocytes of the host brain could be activated early, immediately after surgery, and could directly provide glucose for the transplanted cells via glycogenolysis (Forno et al., 1992), thereby reducing the metabolic damage caused by the preparation of the material for grafting. In the longer term, astrocytes also mediate the vascularization of grafted tissue. The commonly used protocol for preparation of a single cell suspension (Pruszak et al., 2009) yields a completely avascular graft. Therefore, the formation on a vascular bed to the graft is a critical stage in its integration. The trauma from the transplantation itself can be viewed as a major vasculogenic stimulus in the CNS (Ment et al., 1997), with astrocytes playing a key role in the formation of the basal lamina of the newly formed vascular endothelium (Lawrence et al., 1984), also interacting with pericytes (Silver and Miller, 2004). On a morphological level this is best demonstrated by the dense astroglial envelope around graft-associated blood vessels (Tomov et al., 2018). The perivascular astrocytic elements are predominantly derived from astrocytes of the host striatum, activated by the transplantation, with lesser numbers being derived from cells in the grafted suspension (Krum and Rosenstein, 1989). This once again speaks for the activation of host astrocytes by grafted cells, promoting organotypic graft development and integration.

Recently, it has been suggested that transplantation of neural stem cells in a model of PD leads to astrocyte‐dependent activation via the canonical Wnt pathway. Ultimately, this leads to activation of neurotrophic and anti‐inflammatory/anti‐oxidant mechanisms, which reduce neuroinflammation and initiate a neurorestorative program for dopaminergic neurons (L’Episcopo et al., 2018). This suggests that astrocytes might mediate indirect effects of transplantation, which generally improves the metabolic state of the CNS, implicates a great, previously unexplored potential of cell-replacement therapies, not only for PD, but also for other neurological disorders.

Evidence suggests that astrocytes are key players in the restoration of the dopaminergic circuitry after grafting in PD. The intensive astrogliosis, surrounding grafts, which can resemble scarring, is in fact isomorphic, and is extremely important for the integration of the transplanted cells. The stimulation by the graft, facilitating axonal outgrowth, synaptic formation, and vascularization, greatly outweighs the activation by the mechanical tissue disruption. Moreover, astrocytes can mediate neuroprotective, neurotrophic, and immunomodulatory effects beneficial for endogenous dopaminergic neurons, by mechanisms not directly involved with reinnervation by the graft

  Microglia and Transplantation Top

Following any mechanical intervention to the CNS, microglia rapidly engage in the neuroinflammatory response. Upon functional activation, they undergo morphological changes and get involved in phagocytosis, respectively antigen presentation, the production and secretion of reactive oxygen species, multitude of cytokines and growth factors (Appel et al., 2010). Grafting to the CNS also inevitably causes activation of the host’s microglia. Like in the case with astroglia, we consider this to be a two-staged process, involving both the tissue trauma from the transplantation itself, as well as the immune reaction against the grafted cells, the latter involving both the innate and the adaptive immunity (Tomov et al., 2019).

Microglial cells are rapidly activated upon disruption of neural tissue; they migrate towards the broken glia limitans, project their processes and act together with astrocytes to restore its integrity (Corps et al., 2015). Experimental data shows that pharmacological blocking of microglial reactivity leads to reduced migration, and subsequently to exacerbation of the tissue injury (Nimmerjahn et al., 2005; Davalos et al., 2005; Haynes et al., 2006; Koizumi et al., 2007). Despite this, the consensus is that acute microglial response is generaly neuroprotective (Roth et al., 2004), while prolonged microglial activation is considered maladaptive (Zhang et al., 2014). Therefore, when discussing the role of microglial cells in post-transplantation events, attention should be given to the mode of microglial activation.

Different activation status of microglial cells can promote either neurotoxicity or neuroprotection (Appel et al., 2010). The classically activated M1 microglial cells secrete pro-inflammatory cytokines and reactive oxygen species, thereby being neurotoxic. At the same time, the alternatively activated M2 microglial cells assist in inflammation resolution by neurotrophic factor release (Michelucci et al., 2009). Very interesting in this context is the cross talk between microglia and T lymphocytes. It is a regulatory mechanism, which can trigger either the classical or the alternative activation pathway of microglial activation, thereby switching the reaction towards a less inflammatory and neuroprotective profile (Appel et al., 2010). In PD, the activation of the microglia classically follows the M1 phenotype, ultimately leading to the cell death of the microglia-surrounded dopaminergic neurons (McGeer et al., 1988; Hald and Lotharius, 2005). The process is associated with significant immune cell activation in the substantia nigra and along the nigrostriatal pathway (McGeer et al., 1988; Appel et al., 2010). It is not certain if exactly the same immunological processes affecting endogenous neurons in PD can also affect the transplanted neurons in cell replacement therapy. It has been proposed that Lewy body pathology, which was observed in grafts in a PD model, is a reaction to inflammation at the graft-host interface, and is mediated by microglia (Gao et al., 2008, George et al., 2019).

We consider the mechanisms involved in neurodegeneration in PD to be also involved in the observed massive degeneration of transplanted dopaminergic neurons (Barker et al., 1996), and at least some of them to be microglia-mediated. Following transplantation, microglial activation is dependent on immunological compatibility between graft and host, the way of delivery of transplantation material, the presence or absence of anti-inflammatory therapy, and the degree of synaptic integration between graft and host.

It has been suggested, that there are two mechanisms of microglial recruitment following grafting (Tomov et al., 2019). The first one is a migration of cells of bone marrow origin to the brain (Ginhoux and Prinz, 2015), and the second is the proliferation of resident microglia. The reported increased permeability of graft-associated blood vessels for several days after transplantation (Akalan and Grady, 1994) is а prerequisite for extravasation of blood-borne cells, which transform into microglia. However, the contribution of such cells to the microglial population of the adult CNS is relatively small. The main mechanism of microglial recruitment is the proliferation of brain microglia (Ginhoux and Prinz, 2015), i.e. the majority of microglial cells surrounding grafts are indeed progeny of resident cells.

Microglial cells have been described infiltrating the transplants as soon as 3 days after grafting (Wenker and Pitossi, 2019). Microglial cells with activated (ameboid) appearance surround grafts and infiltrate the graft core. The microglial infiltration persists for a very significant amount of time post-grafting (Shinoda et al., 1996).

The data regarding the duration of acute microglial activation following grafting is not unambiguous, with reactive microglia persisting for years in cases of patients receiving a graft (Olanow et al., 2003). The notion that acute events should account for retaining the activated phenotype of microglia for only about 10 days (Harry and Kraft, 2012) suggests that grafting accounts for a sustained, prolonged microglial activation.

The degree of microglial infiltration directly correlates with the degree of rejection (Kelly et al., 2004). However, merely the ameboid appearance, being suggestive for an activated phenotype of microglia, does not correlate with expression of CD68, which would hint towards phagocytic activation (Li et al., 2008). The presence of activated microglia around and within grafts, therefore, is not directly equal to processes of graft rejection and is normally seen in “healthy” grafts (Kordower et al., 1997). This microglia should be classified as M2-activated. It is clear though that e.g. immunological incompatibility between donor and recipient is likely to induce a rejection, manifested as a long-lasting inflammatory response accompanied by M1 activation of microglia and macrophages.

For a long time, the brain had been considered to be an organ out of the vigilance of the immune system. Therefore, it has been assumed, that cell transplants into the brain would not need immonsuppressive therapy. However, experiments have shown that the CNS is not absolutely immunopriviledged, and transplants to the brain are indeed immunogenic (Barker and Widner, 2004). Clinical evidence clearly demonstrates that in allogeneic transplantation, immunosuppression is necessary, in order to achieve survival of grafts (for a review see Winkler et al., 2005). Moreover, immunological provocation has been strongly associated to graft rejection (Piquet et al., 2012). This indicates that activated microglial cells observed after grafting are involved in an ongoing immune-mediated inflammatory process.

A major activator for microglia could be the donor blood vessels expressing high levels of the major histocompatibility complex (MHC) class I molecules (Finsen et al., 1991). The preparation of suspension grafts usually destroys those vascular structures, shifting the equilibrum towards host-driven angiogenesis (Mendez et al., 2005; Cooper et al., 2009) and at the same time fundamentally reducing immunogenicity. In those instances, the most intensive microglial reaction remains along the needle tract (Mendez et al., 2005), probably due to the tissue trauma itself. The reports of MHC class II upregulation and intensive microglial response to transplants of solid tissue pieces in Parkinson’s disease patients (Kordower et al., 1997; Freed et al., 2001) also suggest that preparation of a single-cell suspension is a good strategy to evade a major microglia-driven neuroinflammation. Thereby, the amount of non-neural elements in the material to be transplanted should be maximally reduced. In this direction, it has been proposed that MHC graft-host matching along with immunosuppression is the best strategy to evade immune rejection of intracerebral grafts. This strategy significantly reduces, but does not completely neutralize the microglial reaction (Morizane et al., 2017). Activation of microglia can be attributed to the existence of MHC-independent antigens (Mizukami et al., 2014). However, the great complexity of events around the intracerebral graft leaves room for other non-immunological mechanisms of microglial activation, such as synaptic formation, which will be discussed later in the present work.

Intensive microglial recruitment along the graft-host interface is known to correlate with worse functional outcome, despite not directly being associated with graft rejection (Winkler et al., 2005). Evidence points towards the notion that excessive microglial activation leads to aberrant synaptic formation, associated with the development of graft-induced diskynesias (Soderstrom et al., 2005) – a much-feared complication in the clinical application of cell therapy. Pro-inflammatory cytokines have been associated with a gene expression pattern, consistent with activation (Kyriakis and Avruch, 1999), such as the upregulation of FosB/ΔFosB, a transcription factor upregulated in animal models of dyskinesias (Cenci, 2002; Maries et al., 2006). Therefore, the participation of microglia in the development of graft-induced dyskinesias remains an open topic to provide transplant recipients with good quality of life.

In one of the clinical studies with intracerebral dopaminergic transplantation, patients with seemingly functional grafts deteriorated quickly after withdrawal of immunosuppression, with a postmortem finding of extensive microglial infiltration of the grafts (Olanow et al., 2003). Moreover, the expression level of general markers of immune response has been correlated with the degree of deterioration of grafts with poorer functional outcome (Kordower et al., 2008). Therefore, it is certain that successful engraftment of (allogeneic) dopaminergic grafts without systemic immunosuppression is extremely difficult to obtain.

Despite the obvious benefits, continuous immunosuppression in a clinical setting leads to considerable morbidity (Piquet et al., 2012). At the same time, it is known that dopaminergic neurons may be beneficed and protected by anti-inflammatory intervention targeting microglia (Barcia et al., 2011). This has sparkled interest towards more specific glia-oriented intervention for enhancing results of dopaminergic transplantation and has shown that selective microglial inhibition is possible (Tomov et al., 2019). While in xenotransplantation, inhibition of microglia is generally beneficial (Michel-Monigadon et al., 2010), the results of Tomov et al. did not show a relationship between extent of microglial recruitment and the number of dopaminergic neurons integrating after transplantation. In this perspective, a longer follow-up of the results of modification of glial reactivity is needed in order to confirm potential applications for enhancing functionality of grafts.

A great body of information clearly shows that microglia is not just “the bad guy” in neuroinflammation. It is known that the activation profile of microglia can be switched from the neurotoxic M1 to the neuroprotective M2 phenotype via several mechanisms, including cytokine-mediated interaction and direct influence by CD4+ regulatory lymphocytes (Comi and Tondo, 2017). This phenomenon has an utter importance for the survival and integration of the graft. Axonal regeneration is known to involve microglial cells (Shokouhi et al., 2010). Furthermore, evidence supports a role for microglia-secreted inflammatory mediators in synaptic plasticity (Leonardo, 2005). Such cytokines can even lead to increased synaptic strength (Bains and Oliet, 2007).

The importance of microglia for forming and maintaining synaptic connections is widely known (Trapp et al., 2007; Wake et al., 2009). The interaction between neurons and microglial cells is bidirectional, and the activity of neurons can directly activate microglia (Hirrlinger et al., 2004; Nimmerjahn et al., 2005; Hung et al., 2010). Activated microglia actively eliminates structures from weakly active synapses (Stellwagen and Malenka, 2006), but is also involved in regeneration of interrupted neural fibres (Prewitt et al., 1997). Dopaminergic neurites, growing beyond the area of a mechanical lesion, are intimately associated with activated macrophages (Batchelor et al., 1999). Those fact suggest that reinnervation of the host brain by the dopaminergic graft is closely related to microglial activity. The observed prolonged microglial activation, persisting for many weeks following grafting (Barker et al., 1996; Stott and Barker, 2013; Tomov et al., 2019) is an indirect evidence for the synaptic integration of the grafted tissue.

Despite we have attempted to give separate accounts of the astroglial and microglial activation, one should keep in mind that the mechanisms of activation of both cell populations are similar. Both astrocytes as well as microglial cells express receptors for the same proinflammatory cytokines (Barcia et al., 2011). Therefore, we can conclude that neuroinflammation itself is also a major stimulus for reactive astrogliosis and perpetuates the glial activation surrounding the graft. The balance between isomorphic astrogliosis, driven by M2 activation of microglia, and glial scarring, caused by microglia with M1 phenotype and the exact molecular mechanisms affecting it is still a topic of discussion.

  What Do We Know and Where Are We Going? Top

Neuropathological data suggests that persistent glial activation in PD may be responsible for perpetuating neuroinflammation and contributing to neuronal degeneration (Barcia et al., 2011). Abundant data also suggests that anti-inflammatory therapy may be beneficial in PD patients (Chen et al., 2005). This can lead us to the conclusion that the mechanisms, involved in glial activation in sporadic PD and following intracerebral transplantation could lead to the same detrimental effects for the dopaminergic neurons. Given that anti-inflammatory therapy elegantly targeting only selected crucial mechanisms might be a promising therapy for many CNS conditions, we believe that manipulating the glial response following intracerebral transplantation is relevant for the applied cell therapy of PD.

Pioneer of dopaminergic transplantation Ole Isacson said “The cell that you would like to transplant is the fetal A9 neuron with appropriate glial support, but we don’t yet have that” (Isacson et al., 2003). Recent advancements from the field of induced pluripotent stem cell research (Stoddard-Bennett and Reijo Pera, 2019) might soon solve the problem with the cell to be transplanted. This gives hope to raise the self-imposed moratorium over the dopaminergic cell transplantation in patients. How exactly a transplantation is “correctly performed”, is still a subject of debate, which should take multiple factors into consideration (Collier et al., 2019). We, as Ole Isacson, suggest that attention should be paid to the glial cells as well, as important players in post-grafting events. Understanding specific mechanisms of glial activation as well of glia-graft interaction means understanding one of the multiple factors, which affect the results of intracerebral transplantation in PD. Only by optimizing the patient’s chance to receive benefit from this procedure we can hope to move past the experimental into the applied setting.[81]

  Conclusion Top

Experimental data shows that the adult brain is a very plastic system, capable of incorporating transplanted neurons into functional systems. After transplantation, host glial cells exert multiple effects, both beneficial and detrimental, as outlined in [Figure 1]. Elucidating the molecular mechanisms of glia-graft interaction should provide clues for developing more effective cell-replacement therapies for the future and lead to better functional results for patients.
Figure 1: A schematic outline of beneficial and detrimental effects of glial activation following intracerebral transplantation.

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Author contributions: The author completed the work independently.

Conflicts of interest: The author declares no conflicts of interest.

Financial support: None.

Copyright license agreement: The Copyright License Agreement has been signed by the author before publication.

Plagiarism check: Checked twice by iThenticate.

Peer review: Externally peer reviewed.

Open peer reviewers: Agustin Cota-Coronado, Medical and Pharmaceutical Biotechnology, Mexico; Cristoforo Comi, University of Piemonte Orientale, Italy.

  References Top

Akalan N, Grady MS (1994) Angiogenesis and the blood-brain barrier in intracerebral solid and cell suspension grafts. Surg Neurol 42:517-522.  Back to cited text no. 1
Appel SH, Beers DR, Henkel JS (2010) T cell-microglial dialogue in Parkinson’s disease and amyotrophic lateral sclerosis: are we listening? Trends Immunol 31:7-17.  Back to cited text no. 2
Bains JS, Oliet SH (2007) Glia: they make your memories stick! Trends Neurosci 30:417-424.  Back to cited text no. 3
Barcia C, Ros CM, Annese V, Gomez A, Ros-Bernal F, Aguado-Yera D, Martinez-Pagan ME, de Pablos V, Fernandez-Villalba E, Herrero MT (2011) IFN-gamma signaling, with the synergistic contribution of TNF-alpha, mediates cell specific microglial and astroglial activation in experimental models of Parkinson’s disease. Cell Death Dis 2:e142.  Back to cited text no. 4
Barker RA, consortium T (2019) Designing stem-cell-based dopamine cell replacement trials for Parkinson’s disease. Nat Med 25:1045-1053.  Back to cited text no. 5
Barker RA, Dunnett SB, Faissner A, Fawcett JW (1996) The time course of loss of dopaminergic neurons and the gliotic reaction surrounding grafts of embryonic mesencephalon to the striatum. Exp Neurol 141:79-93.  Back to cited text no. 6
Barker RA, Widner H (2004) Immune problems in central nervous system cell therapy. NeuroRx 1:472-481.  Back to cited text no. 7
Batchelor PE, Liberatore GT, Wong JY, Porritt MJ, Frerichs F, Donnan GA, Howells DW (1999) Activated macrophages and microglia induce dopaminergic sprouting in the injured striatum and express brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. J Neurosci 19:1708-1716.  Back to cited text no. 8
Björklund A (1999) Transplanted precursors of nerve cells: Das and Altman and the revival of neural transplantation research. Brain Res Bull 50:477-478.  Back to cited text no. 9
Bjorklund A, Stenevi U (1979) Reconstruction of the nigrostriatal dopamine pathway by intracerebral nigral transplants. Brain Res 177:555-560.  Back to cited text no. 10
Cenci MA (2002) Transcription factors involved in the pathogenesis of L-DOPA-induced dyskinesia in a rat model of Parkinson’s disease. Amino Acids 23:105-109.  Back to cited text no. 11
Chen H, Jacobs E, Schwarzschild MA, McCullough ML, Calle EE, Thun MJ, Ascherio A (2005) Nonsteroidal antiinflammatory drug use and the risk for Parkinson’s disease. Ann Neurol 58:963-967.  Back to cited text no. 12
Collier TJ, Sortwell CE, Mercado NM, Steece-Collier K (2019) Cell therapy for Parkinson’s disease: Why it doesn’t work every time. Mov Disord doi: 10.1002/mds.27742  Back to cited text no. 13
Comi C, Tondo G (2017) Insights into the protective role of immunity in neurodegenerative disease. Neural Regen Res 12:64-65  Back to cited text no. 14
Cooper O, Astradsson A, Hallett P, Robertson H, Mendez I, Isacson O (2009) Lack of functional relevance of isolated cell damage in transplants of Parkinson’s disease patients. J Neurol 256 Suppl 3:310-316.  Back to cited text no. 15
Corps KN, Roth TL, McGavern DB (2015) Inflammation and neuroprotection in traumatic brain injury. JAMA Neurol 72:355-362.  Back to cited text no. 16
Das GD, Altman J (1971) Transplanted precursors of nerve cells: their fate in the cerebellums of young rats. Science 173:637-638.  Back to cited text no. 17
Das GD, Altman J (1972) Studies on the transplantation of developing neural tissue in the mammalian brain. I. Transplantation of cerebellar slabs into the cerebellum of neonate rats. Brain Res 38:233-249.  Back to cited text no. 18
Das GD, Nornes HO, Hine RJ, Pfaffenroth MJ (1973) Experimental studies on the postnatal development of the brain. II. Cytoarchitectural regeneration in the developing cerebellum of the rabbit. TIT J Life Sci 3:29-65.  Back to cited text no. 19
Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8:752-758.  Back to cited text no. 20
Ferrer I (2017) Diversity of astroglial responses across human neurodegenerative disorders and brain aging. Brain Pathol 27:645-674.  Back to cited text no. 21
Finsen BR, Sorensen T, Castellano B, Pedersen EB, Zimmer J (1991) Leukocyte infiltration and glial reactions in xenografts of mouse brain tissue undergoing rejection in the adult rat brain. A light and electron microscopical immunocytochemical study. J Neuroimmunol 32:159-183.  Back to cited text no. 22
Forno LS, DeLanney LE, Irwin I, Di Monte D, Langsto JW (1992) Chapter 36: Astrocytes and Parkinson’s disease. In: Neuronal-Astrocytic Interactions: Implications for Normal and Pathological CNS Function (Yu AC, Hertz L, Norenberg MD, Syková E, Waxman SG, eds). Prog Brain Res 94:429-436.  Back to cited text no. 23
Freed CR, Breeze RE, Rosenberg NL, Schneck SA, Kriek E, Qi JX, Lone T, Zhang YB, Snyder JA, Wells TH, et al. (1992) Survival of implanted fetal dopamine cells and neurologic improvement 12 to 46 months after transplantation for Parkinson’s disease. N Engl J Med 327:1549-1555.  Back to cited text no. 24
Gao HM, Kotzbauer PT, Uryu K, Leight S, Trojanowski JQ, Lee VM (2008) Neuroinflammation and oxidation/nitration of alpha-synuclein linked to dopaminergic neurodegeneration. J Neurosci 28:7687-7698.  Back to cited text no. 25
George S, Rey NL, Tyson T, Esquibel C, Meyerdirk L, Schulz E, Pierce S, Burmeister AR, Madaj Z, Steiner JA, Escobar Galvis ML, Brundin L, Brundin P (2019) Microglia affect alpha-synuclein cell-to-cell transfer in a mouse model of Parkinson’s disease. Mol Neurodegener 14:34.  Back to cited text no. 26
Ginhoux F, Prinz M (2015) Origin of microglia: current concepts and past controversies. Cold Spring Harb Perspect Biol 7:a020537.  Back to cited text no. 27
Hald A, Lotharius J (2005) Oxidative stress and inflammation in Parkinson’s disease: is there a causal link? Exp Neurol 193:279-290.  Back to cited text no. 28
Harry GJ, Kraft AD (2012) Microglia in the developing brain: a potential target with lifetime effects. Neurotoxicology 33:191-206.  Back to cited text no. 29
Haynes SE, Hollopeter G, Yang G, Kurpius D, Dailey ME, Gan WB, Julius D (2006) The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci 9: 1512-1519.  Back to cited text no. 30
Hirrlinger J, Hülsmann S, Kirchhoff F (2004) Astroglial processes show spontaneous motility at active synaptic terminals in situ. Eur J Neurosci 20:2235-2239.  Back to cited text no. 31
Hung J, Chansard M, Ousman SS, Nguyen MD, Colicos MA (2010) Activation of microglia by neuronal activity: results from a new in vitro paradigm based on neuronal-silicon interfacing technology. Brain Behav Immun 24:31-40.  Back to cited text no. 32
Isacson O, Bjorklund LM, Schumacher JM (2003) Toward full restoration of synaptic and terminal function of the dopaminergic system in Parkinson’s disease by stem cells. Ann Neurol 53 Suppl 3:S135-146.  Back to cited text no. 33
Isacson O, Deacon TW, Pakzaban P, Galpern WR, Dinsmore J, Burns LH (1995) Transplanted xenogeneic neural cells in neurodegenerative disease models exhibit remarkable axonal target specificity and distinct growth patterns of glial and axonal fibres. Nat Med 1:1189-1194.  Back to cited text no. 34
Koizumi S, Shigemoto-Mogami Y, Nasu-Tada K, Shinozaki Y, Ohsawa K, Tsuda M, Joshi BV, Jacobson KA, Kohsaka S, Inoue K (2007) UDP acting at P2Y6 receptors is a mediator оf microglial phagocytosis. Nature 446:1091-1095.  Back to cited text no. 35
Kordower JH, Chu Y, Hauser RA, Olanow CW, Freeman TB (2008) Transplanted dopaminergic neurons develop PD pathologic changes: a second case report. Mov Disord 23:2303-2306.  Back to cited text no. 36
Kordower JH, Styren S, Clarke M, DeKosky ST, Olanow CW, Freeman TB (1997) Fetal grafting for Parkinson’s disease: expression of immune markers in two patients with functional fetal nigral implants. Cell Transplant 6:213-219  Back to cited text no. 37
Krum JM, Rosenstein JM (1989) The fine structure of vascular-astroglial relations in transplanted fetal neocortex. Exp Neurol 103:203-212.  Back to cited text no. 38
Kyriakis JM, Avruch J (1996) Sounding the alarm: protein kinase cascades activated by stress and inflammation. J Biol Chem 271:24313-24316.  Back to cited text no. 39
L’Episcopo F, Tirolo C, Peruzzotti-Jametti L, Serapide MF, Testa N, Caniglia S, Balzarotti B, Pluchino S, Marchetti B (2018) Neural stem cell grafts promote astroglia-driven neurorestoration in the aged Parkinsonian brain via wnt/beta-catenin signaling. Stem Cells 36:1179-1197.  Back to cited text no. 40
Lawrence JM, Huang SK, Raisman G (1984) Vascular and astrocytic reactions during establishment of hippocampal transplants in adult host brain. Neuroscience 12:745-760.  Back to cited text no. 41
Le Gros Clark WE (1940) Neuronal differentiation in implanted foetal cortical tissue. J Neurol Psychiat 3:263-284.  Back to cited text no. 42
Leonardo A (2005) Degenerate coding in neural systems. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 191:995-1010.  Back to cited text no. 43
Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, Lashley T, Quinn NP, Rehncrona S, Bjorklund A, Widner H, Revesz T, Lindvall O, Brundin P (2008) Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med 14:501-503.  Back to cited text no. 44
Li Y, Li D, Ibrahim A, Raisman G (2012) Repair involves all three surfaces of the glial cell. Prog Brain Res 201:199-218.  Back to cited text no. 45
Maries E, Kordower JH, Chu Y, Collier TJ, Sortwell CE, Olaru E, Shannon K, Steece-Collier K (2006) Focal not widespread grafts induce novel dyskinetic behavior in parkinsonian rats. Neurobiol Dis 21:165-180.  Back to cited text no. 46
McGeer PL, Itagaki S, McGeer EG (1988) Expression of the histocompatibility glycoprotein HLA-DR in neurological disease. Acta Neuropathol 76:550-557.  Back to cited text no. 47
Mendez I, Sanchez-Pernaute R, Cooper O, Vinuela A, Ferrari D, Bjorklund L, Dagher A, Isacson O (2005) Cell type analysis of functional fetal dopamine cell suspension transplants in the striatum and substantia nigra of patients with Parkinson’s disease. Brain 128:1498-1510.  Back to cited text no. 48
Mendez I, Vinuela A, Astradsson A, Mukhida K, Hallett P, Robertson H, Tierney T, Holness R, Dagher A, Trojanowski JQ, Isacson O (2008) Dopamine neurons implanted into people with Parkinson’s disease survive without pathology for 14 years. Nat Med 14:507-509.  Back to cited text no. 49
Ment LR, Stewart WB, Fronc R, Seashore C, Mahooti S, Scaramuzzino D, Madri JA (1997) Vascular endothelial growth factor mediates reactive angiogenesis in the postnatal developing brain. Brain Res Dev Brain Res 100:52-61.  Back to cited text no. 50
Michel-Monigadon D, Nerrière-Daguin V, Lévèque X, Plat M, Venturi E, Brachet P, Naveilhan P, Neveu I (2010) Minocycline promotes long-term survival of neuronal transplant in the brain by inhibiting late microglial activation and T-cell recruitment. Transplantation 89:816-823.  Back to cited text no. 51
Michelucci A, Heurtaux T, Grandbarbe L, Morga E, Heuschling P (2009) Characterization of the microglial phenotype under specific pro-inflammatory and anti-inflammatory conditions: Effects of oligomeric and fibrillar amyloid-beta. J Neuroimmunol 210:3-12.  Back to cited text no. 52
Mizukami Y, Abe T, Shibata H, Makimura Y, Fujishiro SH, Yanase K, Hishikawa S, Kobayashi E, Hanazono Y (2014) MHC-matched induced pluripotent stem cells can attenuate cellular and humoral immune responses but are still susceptible to innate immunity in pigs. PLoS One 9:e98319.  Back to cited text no. 53
Morizane A, Kikuchi T, Hayashi T, Mizuma H, Takara S, Doi H, Mawatari A, Glasser MF, Shiina T, Ishigaki H, Itoh Y, Okita K, Yamasaki E, Doi D, Onoe H, Ogasawara K, Yamanaka S, Takahashi J (2017) MHC matching improves engraftment of iPSC-derived neurons in non-human primates. Nat Commun 8:385.  Back to cited text no. 54
Nikkhah G, Olsson M, Eberhard J, Bentlage C, Cunningham MG, Bjorklund A (1994) A microtransplantation approach for cell suspension grafting in the rat Parkinson model: a detailed account of the methodology. Neuroscience 63:57-72.  Back to cited text no. 55
Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314-1318.  Back to cited text no. 56
Olanow CW, Goetz CG, Kordower JH, Stoessl AJ, Sossi V, Brin MF, Shannon KM, Nauert GM, Perl DP, Godbold J, Freeman TB (2003) A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol 54:403-414.  Back to cited text no. 57
Perlow MJ, Freed WJ, Hoffer BJ, Seiger A, Olson L, Wyatt RJ (1979) Brain grafts reduce motor abnormalities produced by destruction of nigrostriatal dopamine system. Science 204:643-647.  Back to cited text no. 58
Petit A, Pierret P, Vallee A, Doucet G (2001) Astrocytes from cerebral cortex or striatum attract adult host serotoninergic axons into intrastriatal ventral mesencephalic co-grafts. J Neurosci 21:7182-7193.  Back to cited text no. 59
Piquet AL, Venkiteswaran K, Marupudi NI, Berk M, Subramanian T (2012) The immunological challenges of cell transplantation for the treatment of Parkinson’s disease. Brain Res Bull 88:320-331.  Back to cited text no. 60
Prewitt CM, Niesman IR, Kane CJ, Houlé JD (1997) Activated macrophage/microglial cells can promote the regeneration of sensory axons into the injured spinal cord. Exp Neurol 148:433-443.  Back to cited text no. 61
Pruszak J, Just L, Isacson O, Nikkhah G (2009) Isolation and culture of ventral mesencephalic precursor cells and dopaminergic neurons from rodent brains. Curr Protoc Stem Cell Biol Chapter 2:Unit 2D 5.  Back to cited text no. 62
Rolls A, Shechter R, Schwartz M (2009) The bright side of the glial scar in CNS repair. Nat Rev Neurosci 10:235-241.  Back to cited text no. 63
Roth TL, Nayak D, Atanasijevic T, Koretsky AP, Latour LL, McGavern DB (2014) Transcranial amelioration of inflammation and cell death after brain injury. Nature 505:223-228.  Back to cited text no. 64
Saltykow S (1905) Versuche über Gehirnplantation, zugleich ein Beitrag zur Kenntniss der Vorgänge an den zelligen Gehirnelementen. Arch Psychiatr Nervenkr 40:329-388.  Back to cited text no. 65
Shinoda M, Hudson JL, Strömberg I, Hoffer BJ, Moorhead JW, Olson L (1999) Microglial cell responses to fetal ventral mesencephalic tissue grafting and to active and adoptive immunizations. Exp Neurol 141:173-180  Back to cited text no. 66
Shokouhi BN, Wong BZ, Siddiqui S, Lieberman AR, Campbell G, Tohyama K, Anderson PN (2010) Microglial responses around intrinsic CNS neurons are correlated with axonal regeneration. BMC Neurosci 11:13  Back to cited text no. 67
Silver J, Miller JH (2004) Regeneration beyond the glial scar. Nat Rev Neurosci 5:146-156.  Back to cited text no. 68
Soderstrom KE, Meredith G, Freeman TB, McGuire SO, Collier TJ, Sortwell CE, Wu Q, Steece-Collier K (2008) The synaptic impact of the host immune response in a parkinsonian allograft rat model: Influence on graft-derived aberrant behaviors. Neurobiol Dis 32:229-242.  Back to cited text no. 69
Stellwagen D, Malenka RC (2006) Synaptic scaling mediated by glial TNF-alpha. Nature 440:1054-1059.  Back to cited text no. 70
Stoddard-Bennett T, Reijo Pera R (2019) Treatment of Parkinson’s disease through personalized medicine and induced pluripotent stem cells. Cells doi: 10.3390/cells8010026  Back to cited text no. 71
Stott SR, Barker RA (2014) Time course of dopamine neuron loss and glial response in the 6-OHDA striatal mouse model of Parkinson’s disease. Eur J Neurosci 39:1042-1056.  Back to cited text no. 72
Thompson WG (1890). Successful brain grafting. N Y Med J 51:701-702.  Back to cited text no. 73
Tomov N, Surchev L, Wiedenmann C, Dobrossy M, Nikkhah G (2019) Roscovitine, an experimental CDK5 inhibitor, causes delayed suppression of microglial, but not astroglial recruitment around intracerebral dopaminergic grafts. Exp Neurol 318:135-144.  Back to cited text no. 74
Tomov N, Surchev L, Wiedenmann C, Dobrossy MD, Nikkhah G (2018) Astrogliosis has different dynamics after cell transplantation and mechanical impact in the rodent model of Parkinson’s disease. Balkan Med J 35:141-147.  Back to cited text no. 75
Trapp BD, Wujek JR, Criste GA, Jalabi W, Yin X, Kidd GJ, Stohlman S, Ransohoff R (2007) Evidence for synaptic stripping by cortical microglia. Glia 5:360-368.  Back to cited text no. 76
Villalba RM, Smith Y (2011) Neuroglial plasticity at striatal glutamatergic synapses in Parkinson’s disease. Front Syst Neurosci 5:68  Back to cited text no. 77
Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura, J (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 29:3974-3980.  Back to cited text no. 78
Wenker SD, Pitossi FJ (2019) Cell therapy for Parkinson’s disease is coming of age: current challenges and future prospects with a focus on immunomodulation. Gene Ther doi: 10.1038/s41434-019-0077-4.  Back to cited text no. 79
Winkler C, Kirik D, Björklund A (2005) Cell transplantation in Parkinson’s disease: how can we make it work? Trends Neurosci 28:86-92.  Back to cited text no. 80
Zhang J, Malik A, Choi HB, Ko RW, Dissing-Olesen L, MacVicar BA (2014) Microglial CR3 activation triggers long-term synaptic depression in the hippocampus via NADPH oxidase. Neuron 82:195-207.  Back to cited text no. 81

C-Editors: Zhao M, Song LP; T-Editor: Jia Y


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