Bone marrow transplants and neurodegeneration
 Read with caution! This post was written during early stages of trying to understand a complex scientific problem, and we didn't get everything right. The original author no longer endorses the content of this post. It is being left online for historical reasons, but read at your own risk. |
Perhaps you, like me, have been wondering what the deal is with bone marrow transplants and what, if any, connection they have to neurodegeneration. From what I can tell there was a flurry of publication on this subject in the early 2000s proposing that adult humans do use hematopoietic stem cells to form new neurons, though only a small number of transplanted cells end up differentiating into neurons (or astrocytes or microglia.) Some researchers suggested that if we could identify factors that especially encourage transplanted cells to turn into neurons, this could facilitate the use of bone marrow transplants as a form of regenerative therapy for the brain.
Some other things I’ve learned recently about bone marrow transplants:
Still fairly risky, in large part because of the complications for your immune system, and risk of graft-versus-host disease. Therefore, pairs well as a treatment with immunodeficiency diseases. If all goes really well, we’re looking at ballpark 90% survival rate (though the numbers are improving all the time.) An immunosuppression regimen is necessary for life.
Interestingly, different societies weigh these risks pretty differently. For example, bone marrow transplants are the standard of care for sickle cell anemia in Europe — not so in the US.
Odds are best if your donor is an HLA-matched sibling (the odds of any given full sibling being an HLA match are 1 in 4.) HLA stands for the Human Leukocyte Antigen system, which is the name for the major histocompatibility complex in humans, which is a major gene locus most relevant to the immune system.
Next best is an HLA match from someone of your same ethnic makeup. This gets tricky, though – the odds of a non-family member being an HLA match are somewhere around 1/10,000. Apparently this is a super heterogeneous part of the genome (which makes sense, I guess, given the need for constantly evolving immune defenses.)
There will be more to say on this subject once I am smarter!
“Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow,” Mezey et al., Science (2000)
Bone marrow stem cells give rise to a variety of hematopoietic lineages and repopulate the blood throughout adult life. We show that, in a strain of mice incapable of developing cells of the myeloid and lymphoid lineages, transplanted adult bone marrow cells migrated into the brain and differentiated into cells that expressed neuron-specific antigens. These findings raise the possibility that bone marrow–derived cells may provide an alternative source of neurons in patients with neurodegenerative diseases or central nervous system injury.
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These studies demonstrate that bone marrow cells migrate into the brain and differentiate into cells that express neuron-specific antigens. In combination with previous in vivo studies (9, 12, 13), the present work suggests that the bone marrow can supply the brain with an alternative source of neural cells. Neurons and macroglia (oligodendrocytes and astrocytes) are thought to arise from pluripotent neural stem cells that are present both in the developing (30) and adult mammalian CNS (31-35). It has been estimated that, for every 2000 existing neurons, one new neuron is produced each day (35, 36)…Two populations of neural stem cells have been identified in adult mammals: one in the ependymal cell layer lining the ventricles (33) and one in the subventricular zone [glial fibrillary acidic protein-immunoreactive cells (34), each of which gives rise to glial cells and neurons]. We suggest that, in addition to these sources of neural stem cells, there may be a continuous influx of bone marrow stem cells into the ependymal and subependymal zones that give rise to a variety of CNS neural cell types. An interesting possibility is that these entry routes might also serve as portals into the CNS for diseases that primarily originate in and affect the hematopoietic system (i.e., leukemia and AIDS).
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Although our study showed that only a small number of transplanted cells expressed neuronal antigens in the adult brain, there may be factors that promote the differentiation of bone marrow cells into distinct neural cell types. Once these factors are identified, bone marrow cells might be expanded in vitro and provide an unlimited source of cells for the treatment of CNS disease and injury.
“Bone marrow transdifferentiation in brain after transplantation: a retrospective study,” Cogle et al., The Lancet (2004)
http://www.sciencedirect.com/science/article/pii/S0140673604161023
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.
“Transplanted bone marrow generates new neurons in human brains,” Mezey, PNAS (2002)
http://www.pnas.org/content/100/3/1364.short
[W]e decided to examine postmortem brain samples from females who had received bone marrow transplants from male donors.… In all four patients studied we found cells containing Y chromosomes in several brain regions. Most of them were nonneuronal (endothelial cells and cells in the white matter), but neurons were certainly labeled, especially in the hippocampus and cerebral cortex. The youngest patient (2 years old), who also lived the longest time after transplantation, had the greatest number of donor-derived neurons (7 in 10,000). The distribution of the labeled cells was not homogeneous. There were clusters of Y-positive cells, suggesting that single progenitor cells underwent clonal expansion and differentiation. We conclude that adult human bone marrow cells can enter the brain and generate neurons just as rodent cells do. Perhaps this phenomenon could be exploited to prevent the development or progression of neurodegenerative diseases or to repair tissue damaged by infarction or trauma.
“From marrow to brain: expression of neuronal phenotypes in adult mice,” Brazleton et al., Science (2000)
http://www.sciencemag.org/content/290/5497/1775.short
After intravascular delivery of genetically marked adult mouse bone marrow into lethally irradiated normal adult hosts, donor-derived cells expressing neuronal proteins (neuronal phenotypes) developed in the central nervous system. Flow cytometry revealed a population of donor-derived cells in the brain with characteristics distinct from bone marrow. Confocal microscopy of individual cells showed that hundreds of marrow-derived cells in brain sections expressed gene products typical of neurons (NeuN, 200-kilodalton neurofilament, and class III β-tubulin) and were able to activate the transcription factor cAMP response element–binding protein (CREB). The generation of neuronal phenotypes in the adult brain 1 to 6 months after an adult bone marrow transplant demonstrates a remarkable plasticity of adult tissues with potential clinical applications.