October 17, 2003
Bone Marrow Stem Cells Merge With Brain Purkinje Cells

Stem cells merge with brain cells.

STANFORD, Calif. ­ Bone marrow cells can fuse with specialized brain cells, possibly bolstering the brain cells or repairing damage, according to research from the Stanford University School of Medicine. This finding helps resolve an ongoing debate: Do adult stem cells transform from bone marrow cells into other cell types, such as brain, muscle or liver cells, or do they fuse with those cells to form a single entity with two nuclei? The research shows that for complex brain cells called Purkinje cells, fusion is the normal pathway.

Helen Blau, PhD, the Donald E. and Delia B. Baxter Professor of Pharmacology, had previously shown that transplanted bone marrow cells can wind their way up to the brain in humans where they take on characteristics of Purkinje cells – large cells in the part of the brain that controls muscular movement and balance. She had also shown that mature cells in a lab dish can fuse with other cell types and take on characteristics of those cells.

In her most recent work, published in the Oct. 16 advance online issue of Nature Cell Biology, Blau showed that the bone marrow cells in mice fuse with existing Purkinje cells and activate genes normally made in Purkinje cell nuclei. The work will also be published in the November issue of the journal.

“I think that fusion might be a really important biological mechanism,” Blau said. She said researchers previously considered fusion to be less medically important than the idea that bone marrow cells may be able to change fates entirely. Blau disagrees with that assessment. “Fusion might be a sophisticated mechanism for rescuing complex damaged cells,” she said.

Blau and senior research scientist James Weimann, PhD, transplanted mice with bone marrow cells that had been genetically altered to produce a fluorescent green protein. Over the course of the next 18 months (75 percent of a mouse’s life span), they looked for signs of fluorescent green cells in the animals’ brains.

Over time, the group found an increasing number of Purkinje cells that glowed green under a microscope. Looking closely at these cells, they found two nuclei – one from the original Purkinje cell and one from the fused bone marrow cell. They also found that the compact nucleus of the bone marrow cell expanded over time to take on the appearance of the more loosely packed Purkinje cell nucleus.

The Stanford researchers want to develop a better understanding of the signalling process that causes a stem cell to merge with a Purkinje cell in order to be able to find ways to encourage stem cells to merge with damaged brain cells in patients suffering from neurological disorders.

This process of stem cell merger with brain cells also opens up the potential for use of stem cells as a way to deliver better genetic programming in order to do cognitive enhancement and to deliver genes that can undo the effects of aging. If stem cells can be genetically engineered to have genetic variations that enhance cognitive performance then at least some of the existing cells in the brain will be able to be enhanced with genetic variations that will be identified in the future as contributing to intelligence and other aspects of brain function.

There is also an obvious application for trying to reverse some of the general aging of the brain. Genomic decay that occurs with aging could be dealt with at least in part by sending in stem cells to deliver younger nuclei to aged brain cells. Those younger stem cells could also deliver additional genes that would help to basically refurbish aged brain cells. One potential class of genes that could be delivered via this mechanism would be lysosomal enzymes (lysosomes are intracellular organelles that break down waste material in a cell) from other species that are capable of breaking down accumulated intracellular junk that human lysosomal enzymes are unable to break down.

Update: This research is also important because it suggests that adult stem cells may have less potential to differentiate into various cell types than was previously thought.

The adult bone marrow cells appear to fuse with existing cells of the heart, liver and brain rather than differentiating into entirely new ones, the scientists said. The studies suggest that only embryonic cells have the potential to regenerate diseased tissues.

Researchers who were involved with this research caution that clinical trials using adult stem cells are proceeding on a questionable assumption about how those stem cells work. Arturo Alvarez-Buylla of the University of California, San Francisco say past results may have mistakenly been interpreted as evidence of differentiation when fusion was really at work.

According to Morrison and Alvarez-Buylla, their findings offer caution to researchers who have already begun clinical trials in which they are inserting bone marrow cells into damaged heart tissue, in an attempt to regenerate healthy muscle.

"Our findings raise a red flag about going too fast to clinical trials based on the assumption that transdifferentiation is the mechanism by which stem cells give rise to other cell types," said Alvarez-Buylla. "Our paper suggests that previous claims of transdifferentiation may be explained by cell fusion." The scientists said they cannot rule out that transdifferentiation might be occurring, but that they saw no evidence of it in their experimental system.

But if any on-going clinical trials using adult stem cell injection find benefits for people with, for instance, heart disease then it is unlikely the patients will complain just because the benefit comes via a mechanism different than the original mechanism on which the trials were originally justified. There are lots of people with very sick hearts and months left to live who are probably very willing to gamble.

Eventually methods will be developed that will allow cells to be instructed to shift between various types of cells regardless of the starting cell type. Advances in the ability to assay methylation patterns on DNA will allow the tracking of epigenetic state changes and the more rapid development of techniques for causing and controlling the transition of cells into different cell types.

Share |      Randall Parker, 2003 October 17 03:01 PM  Biotech Therapies

michael vassar said at October 18, 2003 11:45 AM:

Aren't all lysosomes pretty similar? If so, I don't see much potential for lysosome enhancement in gene-transfer from eukaryotes. You might be able to put bacterial genes in eukaryotic nuclei and arrange for the production of the relevant proteins in the lysosomes, but this wouln't be easy, especially if the proteins function not directly but by producing catalysts for breaking down junk.

Randall Parker said at October 18, 2003 12:05 PM:

Michael, No, it seems more probable to expect they will differ in their abilities to break stuff down. Organisms differ in their ability to use different compounds as calorie sources. For instance, humans can't break down fiber that other organisms can break down. It seems reasonable to expect that the same pattern will hold for lysosomal enzymes. But we aren't going to know until we start screening lysosomal enzymes from bacteria, molds, and other organisms for their ability to break down stuff our lysosomes can't break down.

As for the difficulty of incorporating lysosomal enzymes from other organisms into a higher eukaryote: it will become easier with time. One problem will probably be to tag the protein product with something that tells the cell to transfer the enzyme to the lysosome. I'm guessing (haven't read up on this) that lysosomes have something analogous to the TIM/TOM machinery for moving nuclear-encoded mitochondrial proteins to the mitochondria. So some stuff will probably have to be added to the lysosomal DNA sequences for lysosomal genes from other species in order to make this work.

Carla Lightfoot said at September 11, 2007 11:43 PM:

Which organelle would be involved in breaking down bone tissue.

Carla Lightfoot said at September 11, 2007 11:46 PM:

A scenario of adding milk, lemon juice and lots of sugar to tea, The tea now has strange white lumps floating in it. What caused the milk to curdle?

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