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Cell fusion in the brain: two cells forward, one cell back.

Kemp K, Wilkins A, Scolding N - Acta Neuropathol. (2014)

Bottom Line: Adult stem cell populations, notably those which reside in the bone marrow, have been shown to contribute to several neuronal cell types in the rodent and human brain.The observation that circulating bone marrow cells can migrate into the central nervous system and fuse with, in particular, cerebellar Purkinje cells has suggested, at least in part, a potential mechanism behind this process.We also highlight how these studies offer new insights into endogenous neuronal repair, opening new exciting avenues for potential therapeutic interventions against neurodegeneration and brain injury.

View Article: PubMed Central - PubMed

Affiliation: Multiple Sclerosis and Stem Cell Group, School of Clinical Sciences, University of Bristol, Neuroscience Office, Learning and Research Building, Southmead Hospital, Bristol, BS10 5NB, UK, kevin.kemp@bristol.ac.uk.

ABSTRACT
Adult stem cell populations, notably those which reside in the bone marrow, have been shown to contribute to several neuronal cell types in the rodent and human brain. The observation that circulating bone marrow cells can migrate into the central nervous system and fuse with, in particular, cerebellar Purkinje cells has suggested, at least in part, a potential mechanism behind this process. Experimentally, the incidence of cell fusion in the brain is enhanced with age, radiation exposure, inflammation, chemotherapeutic drugs and even selective damage to the neurons themselves. The presence of cell fusion, shown by detection of increased bi-nucleated neurons, has also been described in a variety of human central nervous system diseases, including both multiple sclerosis and Alzheimer's disease. Accumulating evidence is therefore raising new questions into the biological significance of cell fusion, with the possibility that it represents an important means of cell-mediated neuroprotection or rescue of highly complex neurons that cannot be replaced in adult life. Here, we discuss the evidence behind this phenomenon in the rodent and human brain, with a focus on the subsequent research investigating the physiological mechanisms of cell fusion underlying this process. We also highlight how these studies offer new insights into endogenous neuronal repair, opening new exciting avenues for potential therapeutic interventions against neurodegeneration and brain injury.

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A bi-nucleate Purkinje cell within the human cerebellum. A 3D confocal image of cells within the human cerebellum immunofluorescently labelled with the Purkinje cell-specific marker Calbindin-D28K (green) and DAPI nuclear stain (blue). The hatched area in a represents the higher magnified image (b) (scale bar 25 μm)
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Fig2: A bi-nucleate Purkinje cell within the human cerebellum. A 3D confocal image of cells within the human cerebellum immunofluorescently labelled with the Purkinje cell-specific marker Calbindin-D28K (green) and DAPI nuclear stain (blue). The hatched area in a represents the higher magnified image (b) (scale bar 25 μm)

Mentions: This unexpected BM-derived cell trans-differentiation into neurons was quickly questioned; the alternative of heterotypic cell fusion and the subsequent transfer of ‘donor’ genetic material to form bi-nucleate heterokaryons (see Fig. 1) was put forward to account for the appearance of donor-derived Purkinje cells [1, 45]. Bi-nucleated neurons have been described in a variety of human CNS pathologies, including Alzheimer’s disease [50], neuro-Behcet’s disease [39], multiple sclerosis [18], Kuru [19] and spino-olivo-ponto-cerebello-nigral atrophy [16]. Historically, as far back as 1939, studies had documented bi-nucleate Purkinje cells in humans [2] (see Fig. 2). Several decades later, reports had also shown that the DNA content of a small percentage of Purkinje cells could be hyperdiploid, with many displaying twice the amount of nuclear DNA of somatic cells [21, 22, 25, 26]. We now know this corroborates quite nicely with what is seen as a result of cellular fusion and the formation of bi-nucleate heterokaryons. However, at the time controversy surrounded these facts and a critical appraisal of the techniques used in those studies claiming a tetraploid DNA content of Purkinje cells strongly contradicted their findings and they were therefore seemingly dismissed [24].Fig. 1


Cell fusion in the brain: two cells forward, one cell back.

Kemp K, Wilkins A, Scolding N - Acta Neuropathol. (2014)

A bi-nucleate Purkinje cell within the human cerebellum. A 3D confocal image of cells within the human cerebellum immunofluorescently labelled with the Purkinje cell-specific marker Calbindin-D28K (green) and DAPI nuclear stain (blue). The hatched area in a represents the higher magnified image (b) (scale bar 25 μm)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4201757&req=5

Fig2: A bi-nucleate Purkinje cell within the human cerebellum. A 3D confocal image of cells within the human cerebellum immunofluorescently labelled with the Purkinje cell-specific marker Calbindin-D28K (green) and DAPI nuclear stain (blue). The hatched area in a represents the higher magnified image (b) (scale bar 25 μm)
Mentions: This unexpected BM-derived cell trans-differentiation into neurons was quickly questioned; the alternative of heterotypic cell fusion and the subsequent transfer of ‘donor’ genetic material to form bi-nucleate heterokaryons (see Fig. 1) was put forward to account for the appearance of donor-derived Purkinje cells [1, 45]. Bi-nucleated neurons have been described in a variety of human CNS pathologies, including Alzheimer’s disease [50], neuro-Behcet’s disease [39], multiple sclerosis [18], Kuru [19] and spino-olivo-ponto-cerebello-nigral atrophy [16]. Historically, as far back as 1939, studies had documented bi-nucleate Purkinje cells in humans [2] (see Fig. 2). Several decades later, reports had also shown that the DNA content of a small percentage of Purkinje cells could be hyperdiploid, with many displaying twice the amount of nuclear DNA of somatic cells [21, 22, 25, 26]. We now know this corroborates quite nicely with what is seen as a result of cellular fusion and the formation of bi-nucleate heterokaryons. However, at the time controversy surrounded these facts and a critical appraisal of the techniques used in those studies claiming a tetraploid DNA content of Purkinje cells strongly contradicted their findings and they were therefore seemingly dismissed [24].Fig. 1

Bottom Line: Adult stem cell populations, notably those which reside in the bone marrow, have been shown to contribute to several neuronal cell types in the rodent and human brain.The observation that circulating bone marrow cells can migrate into the central nervous system and fuse with, in particular, cerebellar Purkinje cells has suggested, at least in part, a potential mechanism behind this process.We also highlight how these studies offer new insights into endogenous neuronal repair, opening new exciting avenues for potential therapeutic interventions against neurodegeneration and brain injury.

View Article: PubMed Central - PubMed

Affiliation: Multiple Sclerosis and Stem Cell Group, School of Clinical Sciences, University of Bristol, Neuroscience Office, Learning and Research Building, Southmead Hospital, Bristol, BS10 5NB, UK, kevin.kemp@bristol.ac.uk.

ABSTRACT
Adult stem cell populations, notably those which reside in the bone marrow, have been shown to contribute to several neuronal cell types in the rodent and human brain. The observation that circulating bone marrow cells can migrate into the central nervous system and fuse with, in particular, cerebellar Purkinje cells has suggested, at least in part, a potential mechanism behind this process. Experimentally, the incidence of cell fusion in the brain is enhanced with age, radiation exposure, inflammation, chemotherapeutic drugs and even selective damage to the neurons themselves. The presence of cell fusion, shown by detection of increased bi-nucleated neurons, has also been described in a variety of human central nervous system diseases, including both multiple sclerosis and Alzheimer's disease. Accumulating evidence is therefore raising new questions into the biological significance of cell fusion, with the possibility that it represents an important means of cell-mediated neuroprotection or rescue of highly complex neurons that cannot be replaced in adult life. Here, we discuss the evidence behind this phenomenon in the rodent and human brain, with a focus on the subsequent research investigating the physiological mechanisms of cell fusion underlying this process. We also highlight how these studies offer new insights into endogenous neuronal repair, opening new exciting avenues for potential therapeutic interventions against neurodegeneration and brain injury.

Show MeSH
Related in: MedlinePlus