Induction and Survival of Binucleated Purkinje Neurons by Selective Damage and Aging

Magrassi, Lorenzo; Grimaldi, Piercesare; Ibatici, Adalberto; Corselli, Mirko; Ciardelli, Laura; Castello, S; Podestà, Marina; Frassoni, Francesco; Rossi, Ferdinando

doi:10.1523/jneurosci.2539-07.2007

Cited by 43 publications

(111 citation statements)

References 22 publications

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“…It is important to note that PKNs remained mononucleated in our study despite intrathecal administration of bacterial lipopolysaccharide and increased microglia numbers. This is in contrast to recent findings by Johansson et al (2008) and Magrassi et al (2007), who used focal cerebellar and inflammatory injury models and found binucleated PKNs. It suggests that the presence of binucleated PKNs in irradiated bone marrow chimeras, which we confirmed in our study, cannot be explained solely on the basis of irradiation-induced inflammation.…”

Section: Discussioncontrasting

confidence: 99%

“…Endogenous cell fusion has been discussed in different contexts, including physiological mechanisms like spermatozoa-ovum fusion, developmental processes like the formation of placenta, bone, and muscle (Potgens et al, 2002;Horsley and Pavlath, 2004;Chen et al, 2007), but also in the context of pathological processes like virus-induced fusion (Price et al, 1988) and tumorigenesis (Bjerkvig et al, 2005). All previous studies dealing with the investigation of fusion events in adult animals have used experimental procedures such as cell transplantation after lethal irradiation, transplantation of cells from syngeneic mice, or parabiotic models to generate chimerism (Wagers et al, 2002;Massengale et al, 2005;Magrassi et al, 2007). However, although these approaches differ significantly in the way they impact the animal, none of these approaches is physiological in a strict sense and therefore limited in establishing the contribution of endogenous BMDCs to other organs.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Fusion of Hematopoietic Cells with Purkinje Neurons Does Not Lead to Stable Heterokaryon Formation under Noninvasive Conditions

Nern

Wolff²,

Macas³

et al. 2009

J. Neurosci.

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Transplanted hematopoietic cells have previously been shown to contribute to cells of other tissues by cell fusion. We wanted to elucidate whether this phenomenon of cell fusion also occurs under physiological conditions. Using a transgenic mouse reporter system to irreversibly label cells of the hematopoietic lineage, we were able to test their contribution to other tissues in the absence of any additional and potentially confounding factors such as irradiation or chemoablation. We found genetically marked, fused Purkinje neurons as well as hepatocytes in numbers comparable to previous bone marrow transplantation studies. The number of fused Purkinje neurons increased after intrathecal administration of bacterial lipopolysaccharide, suggesting that cell fusion can be induced by inflammation. In contrast to previous studies, however, genetically labeled Purkinje neurons never contained more than one nucleus, and we found only a single cell containing two Y-chromosomes in a male mouse. Consistent with results from the mouse model and unlike human bone marrow transplant recipients, postmortem adult human cerebelli of nontransplanted individuals were devoid of binucleated or polyploid Purkinje neurons. Therefore, our data suggests that fusion of hematopoietic cells with Purkinje neurons is only transient and does not lead to stable heterokaryon formation under noninvasive conditions.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Fusion of Hematopoietic Cells with Purkinje Neurons Does Not Lead to Stable Heterokaryon Formation under Noninvasive Conditions

Nern

Wolff²,

Macas³

et al. 2009

J. Neurosci.

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show abstract

“…However, previous work has reported tance of both processes in normal homeostasis and in that neurodegeneration has an important effect in procell replacement therapies for the adult CNS. moting the arrival of BMDC and their fusion with PurMoreover, despite the strong neurodegenerative envikinje cells (3,23,30,38). This difference in the results ronment in both the cerebellum and the OB of PCD mumay be the consequence of differences in the nature and tant mice, neither Purkinje cells nor mitral cells were time course of the neurodegenerative processes and in formed from the transplanted bone marrow.…”

Section: Semmentioning

confidence: 99%

“…Unexpectedly, the neurodegenerative environment had no effect on the behavior of BMDC. In contrast, and generation of Purkinje cells (23,30,38). However, very little is known about the possible plasticity mechanisms very interestingly, the contribution of BMDC occurred through two different plasticity mechanisms, depending for other neuronal types.…”

Section: Introductionmentioning

confidence: 99%

Bone Marrow Contributes Simultaneously to Different Neural Types in the Central Nervous System through Different Mechanisms of Plasticity

et al. 2011

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Many studies have reported the contribution of bone marrow-derived cells (BMDC) to the CNS, raising the possibility of using them as a new source to repair damaged brain tissue or restore neuronal function. This process has mainly been investigated in the cerebellum, in which a degenerative microenvironment has been suggested to be responsible for its modulation. The present study further analyzes the contribution of BMDC to different neural types in other adult brain areas, under both physiological and neurodegenerative conditions, together with the mechanisms of plasticity involved. We grafted genetically marked green fluorescent protein/Cre bone marrow in irradiated recipients: a) the PCD (Purkinje Cell Degeneration) mutant mice, suffering a degeneration of specific neuronal populations at different ages, and b) their corresponding healthy controls. These mice carried the conditional lacZ reporter gene to allow the identification of cell fusion events. Our results demonstrate that BMDC mainly generate microglial cells, although to a lesser extent a clear formation of neuronal types also exists. This neuronal recruitment was not increased by the neurodegenerative processes occurring in PCD mice, where BMDC did not contribute to rescuing the degenerated neuronal populations either. However, an increase in the number of bone marrow-derived microglia was found along the life span in both experimental groups. Six weeks after transplantation more bone marrowderived microglial cells were observed in the olfactory bulb of the PCD mice compared to the control animals, where the degeneration of mitral cells was in process. In contrast, this difference was not observed in the cerebellum, where Purkinje cell degeneration had been completed. These findings demonstrated that the degree of neurodegenerative environment can foster the recruitment of neural elements derived from bone marrow, but also provide the first evidence that BMDC can contribute simultaneously to different encephalic areas through different mechanisms of plasticity: cell fusion for Purkinje cells and differentiation for olfactory bulb interneurons.

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“…Alternative explanations that might posit the generation of stable mouse-rat heterokaryons after cell fusion as described for PCs after bone marrow grafting (18,19), are unlikely because EGFPlabeled PCs maintained mouse morphometric traits, were uninucleated (Fig. S1), and showed appropriate developmental stages in rats killed a few days after grafting (Fig.…”

Section: Discussionmentioning

confidence: 99%

Lifespan of neurons is uncoupled from organismal lifespan

Magrassi

Leto

Rossi

2013

Proc. Natl. Acad. Sci. U.S.A.

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Neurons in mammals do not undergo replicative aging, and, in absence of pathologic conditions, their lifespan is limited only by the maximum lifespan of the organism. Whether neuronal lifespan is determined by the strain-specific lifetime or can be extended beyond this limit is unknown. Here, we transplanted embryonic mouse cerebellar precursors into the developing brain of the longer-living Wistar rats. The donor cells integrated into the rat cerebellum developing into mature neurons while retaining mouse-specific morphometric traits. In their new environment, the grafted mouse neurons did not die at or before the maximum lifespan of their strain of origin but survived as long as 36 mo, doubling the average lifespan of the donor mice. Thus, the lifespan of neurons is not limited by the maximum lifespan of the donor organism, but continues when transplanted in a longerliving host.Purkinje cells | dendrites M edian and maximum lifespan are characteristic of a species. However, whether cellular aging is the major determinant of organismal aging is still debated (1, 2). Replicative aging of continuously dividing cells is well characterized in vitro and in vivo (3). On the contrary, aging of terminally differentiated cells is less characterized and often equated with chronological aging (3). The latter is thought to include all age-related changes in a cell as a result of the stochastic accumulation of structural damage and their functional consequences. Most postmitotic neurons in the mammalian CNS survive aging (4), but specific differences in the lifespan of distinct neuronal populations have been described. Purkinje cells (PCs), the only output neuron of the cerebellar cortex, even in the absence of pathologic conditions, are progressively lost with aging in humans and mice (5, 6).It is not known if a maximum lifespan exists for any postmitotic cells of mammals, including neurons. To address this issue, we exploited the differences in maximum lifespan of different strains of mice and rats. Although the two species have similar aging rates, and, in captivity, under optimal conditions, maximum lifespan of single outbreed individuals may reach 4 y (7), diverse strains of mice and rats differ significantly in their maximum lifespan, and these differences are genetically transmissible (8, 9). In utero, into the developing CNS of embryonic day (E) 15 embryos of Wistar rats, we transplanted cerebellar neuroglial precursors obtained from E12 mice embryos of mixed B6;129Sv background expressing EGFP in all cells (10). After birth of the transplanted rat embryos, we studied if the engrafted mouse cells survived for the entire life of the rat host. ResultsAn outline of the experiment is presented in Fig. 1.Recipient Rats Survived as Long as Two Times the Average Survival of Donor Mice. With the exception of animals electively perfused within 18 mo of life, the remaining graft recipient rats (n = 59; 86%) were let survive until moribund and unlikely to outlive longer than 48 h. Maximum survival of live-born recipient rats w...

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Induction and Survival of Binucleated Purkinje Neurons by Selective Damage and Aging

Cited by 43 publications

References 22 publications

Fusion of Hematopoietic Cells with Purkinje Neurons Does Not Lead to Stable Heterokaryon Formation under Noninvasive Conditions

Fusion of Hematopoietic Cells with Purkinje Neurons Does Not Lead to Stable Heterokaryon Formation under Noninvasive Conditions

Bone Marrow Contributes Simultaneously to Different Neural Types in the Central Nervous System through Different Mechanisms of Plasticity

Lifespan of neurons is uncoupled from organismal lifespan

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