July 10, 2011
RNA Reprograms Brain Cells Into Heart Muscle Cells

Some U Penn researchers injected RNA from heart cells into astrocytes and fibroblasts and in each case the cells converted into the cell type that the RNA came from.

PHILADELPHIA - For the past decade, researchers have tried to reprogram the identity of all kinds of cell types. Heart cells are one of the most sought-after cells in regenerative medicine because researchers anticipate that they may help to repair injured hearts by replacing lost tissue. Now, researchers at the Perelman School of Medicine at the University of Pennsylvania are the first to demonstrate the direct conversion of a non-heart cell type into a heart cell by RNA transfer. Working on the idea that the signature of a cell is defined by molecules called messenger RNAs (mRNAs), which contain the chemical blueprint for how to make a protein, the investigators changed two different cell types, an astrocyte (a star-shaped brain cell) and a fibroblast (a skin cell), into a heart cell, using mRNAs.

James Eberwine, PhD, the Elmer Holmes Bobst Professor of Pharmacology, Tae Kyung Kim, PhD, post-doctoral fellow, and colleagues report their findings online this week in the Proceedings of the National Academy of Sciences. This approach offers the possibility for cell-based therapy for cardiovascular diseases.

Note that the starting cell types were not stem cells. Neither adult or embryonic stem cells were needed as a starting point. This opens up a much longer list of sources of cells to make cell therapies. Continued refinements of techniques to convert cells into other cell types will lead to cell therapies for a great many diseases. Got a bad joint or muscle? Cell therapies are the ticket.

This opens up the possibility of converting just about any cell type to any other cell type.

"What's new about this approach for heart-cell generation is that we directly converted one cell type to another using RNA, without an intermediate step," explains Eberwine. The scientists put an excess of heart cell mRNAs into either astrocytes or fibroblasts using lipid-mediated transfection, and the host cell does the rest. These RNA populations (through translation or by modulation of the expression of other RNAs) direct DNA in the host nucleus to change the cell's RNA populations to that of the destination cell type (heart cell, or tCardiomyocyte), which in turn changes the phenotype of the host cell into the destination cell.

I see potential downsides: If the RNA is from the same person who needs, say, a heart cell therapy it is possible that an undesirable expression pattern of RNA in that person's diseased heart could be replicated in the converted cells. So can one use RNA from a different person's cells to cause the conversion?

Transcriptome Induced Phenotype Remodeling, or TIPeR:

The method the group used, called Transcriptome Induced Phenotype Remodeling, or TIPeR, is distinct from the induced pluripotent stem cell (iPS) approach used by many labs in that host cells do not have to be dedifferentiated to a pluripotent state and then redifferentiated with growth factors to the destination cell type. TIPeR is more similar to prior nuclear transfer work in which the nucleus of one cell is transferred into another cell where upon the transferred nucleus then directs the cell to change its phenotype based upon the RNAs that are made. The tCardiomyocyte work follows directly from earlier work from the Eberwine lab, where neurons were converted into tAstrocytes using the TIPeR process.

There are still more hurdles to making a useful cell therapy. How thorough and complete is the change in cell type? Is there a need to carefully select starting cells to screen out mutations? Does old age of the starter cells make the new cells less able to replicate and function in a heart or other organ?

My guess is that the need to screen the starter cells to identify cells that are not aged is going to be a key problem to solve to make the most effective therapies for older people.

Share |      Randall Parker, 2011 July 10 08:49 AM  Biotech Stem Cells


Comments
Lou Pagnucco said at July 10, 2011 5:33 PM:

Fascinating results.

The full paper is at: http://www.pnas.org/content/early/2011/06/29/1101223108.full.pdf

One particularly interesting excerpt:
"Transcription factor–induced cardiomyocytes also have many characteristics of neonatal cardiomyocytes. Furthermore, carcinogenesis and early senescence often develop in transcription factor–mediated induction of such phenotypic changes."

So, can an old cell can be rewound to its own former, younger phenotype as well?

Also, how high-fidelity are the induced changes to the target cells' epigenetics?

Randall Parker said at July 10, 2011 6:13 PM:

Lou,

I'd like to know whether this transformation lengthens telomeres.

Got 2 radical ideas:

- Save RNA from various cell types from your body right now. Freeze it.

- Freeze some of your cells right now. The younger you do it the better.

That way you can take the cells and program them using younger RNA. Wish I could have done this in my early 20s.

But maybe someone else's youthful RNA would work as well.

John said at July 11, 2011 7:24 AM:

I wonder if freezing young cells is even necessary. A lot of these proteins stick around for some time, especially if cells dry up. Possibly not that much more work to repair the broken mRNA strands.

Just pore through your old scrapbooks, books, etc., and find younger hair, fingerprints, etc., and you're golden!

Lou Pagnucco said at July 11, 2011 9:53 AM:

Randall, John,

Unless I missed it, I see no evidence in the paper that the "transcriptome" must be extracted from juvenile cells. However, it seems plausible that these diverse RNA molecules derived from young cells might give better results.

Good question on telomeres.
Similar questions could be asked about reversal of other cellular changes, e.g.,
- are misfolded/aggregated proteins reduced?
- are defective organelles, like mitochondria, replaced?
- what happens to damaged nuclear pores, nuclear structure, chromatin condensation,...?

Also, the paper leaves unanswered how long that the altered phenotype persists.
Maybe a maintenance treatment is required.

seguin said at July 11, 2011 1:10 PM:

It's been a while since my last GENE class, but as far as I can remember, the youth of the cell that the RNA is culled from shouldn't matter when it comes to telomeres...because telomeres aren't transcribed at all, they're a timing mechanism, an intracellular signal for the timing of cell senescence.

Sherby said at July 12, 2011 3:43 AM:

I don't get it. Why would anyone want their brain turned into a bunch of heart muscle?

Randall Parker said at July 12, 2011 9:16 PM:

Lou,

Trying to replace or reduce a lot of forms of damage in some cell is probably not the way to go. Better to go thru thousands or millions of cells and look for ones that've been lucky and not been much damaged. Damage is very unevenly distributed. What's key is to find cells with minimal DNA damage. Many other forms of damage can be diluted thru cell division.

Sherby,

Lifting up memories to get them out of the way to reach other memories is hard work. Some muscle cells could really help out.

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