Radiation damage increases Purkinje neuron heterokaryons in neonatal cerebellum

Espejel, Silvia; Romero, Rafael Ramírez; Alvarez-Buylla, Arturo

doi:10.1002/ana.21670

Cited by 30 publications

(31 citation statements)

References 34 publications

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“…Possibly a result of too much cellular damage and an overall toxic environment, it is clear that complementary methods will need to be developed to enhance stem cell engraftment and repair, either through fusogenic stem cell rescue or widespread cellular replacement. It is encouraging that recent studies (Johansson et al, 2008; Espejel et al, 2009) support a notion that certain experimental interventions, e.g. radiation/inflammation, can increase stem cell fusion within an at-risk cerebellum.…”

Section: Discussionmentioning

confidence: 96%

Cellular fusion for gene delivery to SCA1 affected Purkinje neurons

Chen

Cruz

Lanuto

et al. 2011

Molecular and Cellular Neuroscience

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Cerebellar Purkinje neurons (PNs) possess a well characterized propensity to fuse with bone marrow-derived cells (BMDCs), producing heterokaryons with Purkinje cell identities. This offers the potential to rescue/repair at risk or degenerating PNs in the inherited ataxias, including Spinocerebellar Ataxia 1 (SCA1), by introducing therapeutic factors through BMDCs to potentially halt or reverse disease progression. In this study, we combined gene therapy and a stem cell-based treatment to attempt repair of at-risk PNs through cell-cell fusion in a Sca1154Q/2Q knock-in mouse model. BMDCs enriched for the hematopoietic stem cell (HSC) population were genetically modified using adeno-associated viral vector 7 (AAV7) to carry SCA1 modifier genes and transplanted into irradiated Sca1154Q/2Q mice. Binucleated Purkinje heterokaryons with sex-mismatched donor Y chromosomes were detected and successfully expressed the modifier genes in vivo. Potential effects of the new genome within Purkinje heterokaryons were evaluated using nuclear inclusions (NIs) as a biological marker to reflect possible modifications of the SCA1 disease process. An overall decrease in number of NIs and an increase in the number of surviving PNs were observed in treated Sca1154Q/2Q. Furthermore, Bergmann glia were found to have fusogenic potential with the donor population and reveal another potential route of therapeutic entry into at-risk cells of the SCA1 cerebellum. This study presents a first step towards a proof of principle that combines somatic cellular fusion events with a neuroprotective gene therapy approach for providing potential neuronal protection/repair in a variety of neurodegenerative disorders.

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Section: Discussionmentioning

confidence: 96%

Cellular fusion for gene delivery to SCA1 affected Purkinje neurons

Chen

Cruz

Lanuto

et al. 2011

Molecular and Cellular Neuroscience

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“…In line with the aim of improving transplantation techniques, the next experiment was based on other studies that show that radiation in newborns increases cell fusion in the cerebellum in a dose‐dependent manner (Espejel et al, ). Then, we irradiated the animals at P2 with 4 Gy, thus in the suggested time frame and with the most effective dose reported (Espejel et al, ). Surprisingly, in wild‐type mice no cell fusion events were detected at P30, which appears to contradict the results obtained by Espejel et al ().…”

Section: Discussionmentioning

confidence: 99%

“…Cell transplants for newborn mice, treated prenatally with busulfan, were carried out intrahepatically (Espejel et al, ) either at P0 or at P4 (for those previously irradiated). Each mouse received a single injection of 7.5 million bone marrow cells from GFP animals.…”

Section: Methodsmentioning

confidence: 99%

Daily bone marrow cell transplantations for the management of fast neurodegenerative processes

Díaz

Pilar

Carretero

et al. 2019

J Tissue Eng Regen Med

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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.

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“…For example, radiation damage of newborn mice increases numbers of binucleated heterokaryons consisting of Purkinje cells fused to bone marrow-derived cells. 31 We hypothesized that transgenic expression of human membrane-bound SCF in the absence of transgenic expression of human GM-CSF as in the NOD-scid triple transgenic stock 17 would enhance human HSC engraftment and permit engraftment of human HSCs without preconditioning irradiation. To test this, we backcrossed the Tg(hu-mSCF) transgene onto the NSG strain and characterized this strain of mice and its ability to support human HSC engraftment.…”

Section: Discussionmentioning

confidence: 99%