Contribution of transplanted bone marrow cells to Purkinje neurons in human adult brains

Abstract

We show here that cells within human adult bone marrow can contribute to cells in the adult human brain. Cerebellar tissues from female patients with hematologic malignancies, who had received chemotherapy, radiation, and a bone marrow transplant, were analyzed. Brain samples were obtained at autopsy from female patients who received male (sex-mismatched) or female (sexmatched, control) bone marrow transplants. Cerebella were evaluated in 10-m-thick, formaldehyde-fixed, paraffin-embedded sections that encompassed up to Ϸ50% of a human Purkinje nucleus. A total of 5,860 Purkinje cells from sex-mismatched females and 3,202 Purkinje cells from sex-matched females were screened for Y chromosomes by epifluorescence. Confocal laser scanning microscopy allowed definitive identification of the sex chromosomes within the morphologically distinct Purkinje cells. In the brains of females who received male bone marrow, four Purkinje neurons were found that contained an X and a Y chromosome and two other Purkinje neurons contained more than a diploid number of sex chromosomes. No Y chromosomes were detected in the brains of sex-matched controls. The total frequency of male bone marrow contribution to female Purkinje cells approximated 0.1%. This study demonstrates that although during human development Purkinje neurons are no longer generated after birth, cells within the bone marrow can contribute to these CNS neurons even in adulthood. The underlying mechanism may be caused either by generation de novo of Purkinje neurons from bone marrow-derived cells or by fusion of marrow-derived cells with existing recipient Purkinje neurons.stem cell ͉ plasticity ͉ cell fusion ͉ cell fate change I n humans, bone marrow has been reported to contribute to human epithelium and liver, but not to the brain (1, 2). Here we investigated whether bone marrow-derived cells could cross the blood-brain barrier and contribute to neurons in the CNS. Previous studies in mice have shown that bone marrow-derived cells can contribute to neuronal cell types in the CNS, including a class of highly specialized neurons in the brain, the Purkinje neurons (3-5).Purkinje neurons are generated only during early brain development. In humans, generation of Purkinje neurons starts at 16 weeks of gestation and is complete by the end of the 23rd week (6). Most of the maturation of the characteristic dendritic trees of human Purkinje neurons is finalized during the first year of life (7). By contrast to other neurons in the adult brain, there is no evidence for the generation of new Purkinje neurons after birth, even in cases of severe Purkinje cell loss caused by trauma or genetic disease (8, 9).The human brain contains Ϸ15 million Purkinje cells, which are among the largest neurons in the CNS (10). A typical Purkinje neuron has Ͼ50-fold the volume of neighboring neurons in the brain, and its complex dendritic extensions receive inputs from as many as one million granule cells. Purkinje cells play vital roles in maintaining balance and regulating movement. A loss o...

Extensive fusion of haematopoietic cells with Purkinje neurons in response to chronic inflammation

“…Nonetheless, in mice with a lethal recessive liver disease (tyrosinaemia), transplantation of wild type BMDCs restored liver function by cell fusion and rescued the mice from death 3, 9 , indicating that cell fusion can have beneficial effects. Here we report that chronic inflammation resulting from severe dermatitis or autoimmune encephalitis leads to robust fusion of BMDCs with Purkinje neurons and formation of hundreds of binucleate heterokaryons, a 10-100 fold higher frequency than previously reported 8,10,11,14 . Single haematopoietic stem cell transplants showed that the fusogenic cell is in the haematopoietic lineage and parabiosis experiments revealed that fusion can occur without irradiation.…”

“…Such fusion events are not limited to rodents, but have also been observed in humans 10 . Purkinje neurons have extensive dendritic arbours with synapses to hundreds of thousands of other neurons.…”

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AbstractTransplanted bone marrow derived cells (BMDCs) have been reported to fuse with cells of diverse tissues [1][2][3][4][5][6][7][8][9][10][11][12][13] , but the extremely low frequency of fusion has led to the view that such events are biologically insignificant. Nonetheless, in mice with a lethal recessive liver disease (tyrosinaemia), transplantation of wild type BMDCs restored liver function by cell fusion and rescued the mice from death 3, 9 , indicating that cell fusion can have beneficial effects.

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“…cells of a number of tissues including skeletal muscle, liver, intestine, and brain 1,3,4,[8][9][10][11][12] . However, the low incidence of fusion, which increases somewhat with tissue damage 2,4,18 , has raised questions regarding its significance 19 .…”

Cellules souches tissulaires adultes :seing is not being

“…[42,43]. Ce mécanisme contribue effectivement au chimérisme observé après greffe de moelle osseuse dans des organes comme le cerveau [55,56] ou le foie [45,46]. Il semble que ce processus fusionnel suffise à lui seul à expliquer la restauration de la fonction hépatique des souris FAH -/-après greffe de moelle; ce ne serait pas le cas dans le cerveau, le muscle ou d'autres épithéliums, où un autre mécanisme interviendrait également; mais les difficultés techniques rencontrées dans l'évaluation de la ploï-die des noyaux incitent à la prudence.…”