Elsevier

The Lancet

Volume 363, Issue 9419, 1 May 2004, Pages 1432-1437
The Lancet

Mechanisms of Disease
Bone marrow transdifferentiation in brain after transplantation: a retrospective study

https://doi.org/10.1016/S0140-6736(04)16102-3Get rights and content

Summary

Background

End-organ repair by adult haemopoietic stem cells is under great scrutiny with investigators challenging the notion of these cells' plasticity. Some investigations of animals and short-term human bone marrow transplants suggest that bone marrow can repair brain. We looked for evidence of clinically relevant marrow-derived restorative neurogenesis: long-term, multilineage, neural engraftment that is not the result of cell-fusion events.

Methods

We examined autopsy brain specimens from three sex-mismatched female bone-marrow-transplantation patients, a female control, and a male control. We did immunohistochemistry, fluorescence in-situ hybridisation, and tissue analysis to look for multilineage, donor-derived neurogenesis.

Findings

Hippocampal cells containing a Y chromosome were present up to 6 years post-transplant in all three patients. Transgender neurons accounted for 1% of all neurons; there was no evidence of fusion events since only one X chromosome was present. Moreover, transgender astrocytes and microglia made up 1–2% of all glial cells.

Interpretation

Postnatal human neuropoiesis happens, and human haemopoietic cells can transdifferentiate into neurons, astrocytes, and microglia in a long-term setting without fusing. Transplantable human haemopoietic cells could serve as a therapeutic source for long-term regenerative neuropoiesis.

Introduction

Adult haemopoietic stem cells can self-renew and differentiate into cells of all haemopoietic lineages. However, there has been great debate about the plasticity of adult stem cells, with some investigators1, 2 challenging the potential for transdifferentiation reported by others.3, 4, 5, 6 These differences between findings might be explained by disparities in haemopoietic stem-cell separation, cell cycle of transplanted cells, time from transplantation to examination for end-organ chimerism, injury eliciting plasticity, and ability of the target niche to support transdifferentiation in these stem cells.7 In addition to poor reproducibility, two other confounding issues should be addressed when considering plasticity: proper cell identification and cell fusion.8, 9 Both issues arise from reliance on single markers to track cell fate.

Murine bone marrow can differentiate into neurons and glial cells in the adult mouse brain, and human bone marrow cells can contribute to the regeneration of the adult rat brain.10, 11, 12, 13, 14 Whether adult neurogenesis affects cognitive function is unknown, but environmental influences such as ischaemia, seizure, and even learning and exercise can substantially stimulate hippocampal neuropoiesis.15, 16, 17, 18 Short-term donor chimerism has been detected in the brains of female bone-marrow-transplant patients,19 but this study only examined one cell lineage and did not rule out fusion. If multilineage neuronal differentiation and long-term repopulation exist, crucial, clinically relevant questions follow. We investigated whether adult human haemopoietic cells can contribute to long-term adult human neuropoiesis without fusing.

Section snippets

Patients

We obtained post-mortem brain samples from three women who received therapeutic transplantation of haemopoietic stem cells from sibling male donors. All samples were obtained with approval from the University of Florida institutional review board and in full compliance with Health Insurance Portablility and Accountablility Act regulations. No personal patient identifiers were requested or provided for the samples. The first case was a 45-year-old white woman with a history of acute myelogenous

GLOSSARY

cell fusion
The melding of two or more cells into one cell. When undifferentiated stem or progenitor cells fuse with mature differentiated cells, the resultant cell can retain the mature cell phenotype.
fluorescence in-situ hybridisation (fish)
FISH can be used to tag specific chromosomes with unique fluorescent dyes. Chromosome number and identity within an individual cell can then be established by fluorescent microscopy. It is a powerful tool to distinguish between cellular transdifferentiation

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