I find following both stem cell news and the stream of interesting publications to be kind of fun and thought-provoking.
This past week or two has been very busy. Here is a news summary and list of notable pubs.
Stem Cell News on Parkinson’s Disease
There were a number of interesting developments on the Parkinson’s Disease front.
Over at STAT News, Sharon Begley wrote about a “secret” experiment in this piece: A secret experiment revealed: In a medical first, doctors treat Parkinson’s with a novel brain cell transplant. The idea here is to make induced pluripotent stem cells or iPS cells and differentiate them into dopamine-producing neurons to treat patients with Parkinson’s.
Many groups are working this area in Japan, the U.S., and elsewhere. For instance, in Japan Jun Takahashi launched an IPS cells for Parkinson’s clinical trial a couple years back.
It’s a great story from Begley, but a few complicated and puzzling things came to mind. First, why the secret? If you have FDA approval, why not be open. In my view secret clinical science is generally not a good way to go for many reasons. The other thing was why take the protein-based reprogramming approach to make iPS cells? I suppose it’s a fine way to go as a non-genetic method, but if the protein angle was your bottleneck, then why not switch?
Does Freezing Change Cells including Stem Cells?
There’s also some stem cell news on a more technical note, but with big clinical implications. We cell biologists routinely freeze our cells, but how sure can we be that when we thaw them that they haven’t changed in important ways? It’s a crucial question and there isn’t enough data on it.
In a classic paper in Stem Cells, first author Guido Moll and a team led by Katarina LeBlanc tackle this for MSCs. The paper, entitled, Do Cryopreserved Mesenchymal Stromal Cells Display Impaired Immunomodulatory and Therapeutic Properties? has some notable findings. The short answer to the question of their title is, “Yes.” The key take-home from the paper, “We found that freeze‐thawed MSCs, as opposed to cells harvested from continuous cultures, have impaired immunomodulatory and blood regulatory properties.”
See Fig. 1A above showing that the frozen cells also trigger an immune reaction described as, “Freeze‐thawed MSCs elicit an increased triggering of the instant blood mediated inflammatory reaction (IBMIR).” IBMIR is probably not a good thing to have happen inside patients’ bodies.
Stem Cells for COVID-19
It’s good to see another call for more careful approaches to the general of stem cells for COVID-19. Here is a pub from a team led by Daniel J. Weiss we have in Cytotherapy, “Cell-Based Therapies for COVID-19: Proper Clinical Investigations are Essential.” As readers of The Niche know I’ve been very concerned about hype and even reckless statements surrounding unproven cell therapies for COVID-19. You can see some of my concerns here.
And some recent notable stem cell papers
- Tools and Concepts for Interrogating and Defining Cellular Identity, Cell Stem Cell
- Unique properties of a subset of human pluripotent stem cells with high capacity for self-renewal, Nature Communications
- The Rational Development of CD133-Targeting Immunotherapies for Glioblastoma, Cell Stem Cell
- Loss of Cxcr5 alters neuroblast proliferation and migration in the aged brain, Stem Cells
- Myogenic Progenitor Cell Lineage Specification by CRISPR/Cas9-Based Transcriptional Activators, Stem Cell Reports
- Synthetic alternatives to Matrigel, Nature Reviews Materials
- Next-generation stem cells — ushering in a new era of cell-based therapies, Nature Reviews Drug Discovery (Erin Kimrel & Robert Lanza)
There are a lot of variables which can affect the cells during the cryopreservation process. How the cells are lifted (what reagents, concentration, how long, etc.), how the cells treated after lifting (washed, diluted, etc.), what the cryoprotectant is or its concentration (home brews notorious lack standardization), how cells are frozen (controlled rate, linear device, dump-freeze), what temperature the cells are stored at (and how stable those temps are), how the cells are thawed, and finally how the thawed cells are handled all have major implications in the heath and wellbeing of any cell type.
The final point ‘how thawed cells are handled’ in my opinion is often one of the most overlooked variables, and one of the most impactful. If you thaw, wash, and just jump into your experiment its almost guaranteed to have a negative impact on the efficacy of those cells. To use a Star Wars analogy, when Han Solo is thawed from carbonite he’s in rough shape. Sure he’s still Han Solo, and he helps defeat the Empire after some time to get back to his normal awesome self… but there on Tatooine facing Jabba the Hut and gang he’s all but useless. The analogy works well for many thawed cells, as the damage incurred by the lifting and freezing and thawing can all compound.
What would be good to see is optimization and standardization many of these variables. Then give the cells time to repair, perhaps with 24-48 in culture. Give time to rebuild internal and external component, ramp up intracellular production, and allow the cells to get back into a growth phase. Time to recover from the carbonite. Then run those cells against fresh counterparts.
Until such time as more of these variables are dealt with, any conclusions can’t be painted generally to MSC’s or any cell type for any of these functional tests, at least beyond those exact conditions used. Another set of variables with the same test could very well yield entirely different results. It’s dangerous to say “Thawed MSC’s are different” otherwise, as again its “Thawed MSC’s are different when we treat them this way”.
Thanks for your comment, Matt. I like your Han Solo thawing analogy.
From growing cells for 30 years I do think freezing and thawing changes them, at the very least temporarily and probably sometimes permanently. More studies of this kind are needed to be sure.
And I think that’s the beauty of science. We can speculate and pull up anecdotal observations, but until we put it to the test it is just that, anecdotal. Most labs have a set methodology that works well enough for some forms of research, but might be lacking for others. Or have an effect that yields the results that lead to an overgeneralization. Its the issue we have in so many areas of cell culture. Lot to lot of FBS is a great example and the move to xeno-free characterized media, and the issues any of those may cause, for example.
For example, I’ve seen papers saying ‘you can’t get viable cells from frozen tissue’ which I’ve been doing for years in my little lab. Their methodology was different from mine, but the publication and results overgeneralized their findings. I know we all understand that the methodology may limit how far we can generalize our findings, so we take if for granted. The problem then becomes people cite the paper, and the papers that cite those papers, as scientific ‘fact’.
One thing the whole industry needs to do more of, from basic research to applies cellular therapies, is address some of the methodologies we’ve all used for so long and realize they may need to be updated. It’s like at the end of Back to the Future when Doc is taking Marty into the future… Marty goes “Doc, we don’t have enough road” and Doc lowers his shades and coolly smiles “Roads, where we’re going we don’t need roads” as the DeLorean transforms and flies off.
Still the paper is highly informative, and just reinforces the need for more research into all of cryopreservation and cell culture. I look forward to the joint ISCT-AABB taskforce on standardizing stability studies and think that will make a good launching point for some of this work.
I think the Princess Bride is maybe a better illustration of your point. Miracle Max brings back Westley from being “mostly dead” and it takes him a pretty big hunk of the final act to do anything (and even then it’s mainly superficial).
Another great analogy, and a great point. There are numerous Sci-fi and Fantasy movies where a hero comes back from the dead. Sometimes they need time to recover, other times they are in peak fighting from right from the get go. Sure it depends on the need of the script… but all the methodologies vary. Avenger’s Endgame shows ‘The Snap’ to bring everyone back ready for the big fight.
So for those in the field of cryopreservation perhaps the holy grail to be searched for a methodology that preserves all of (or most of) the functionality of cells. Of course it might not exist, but that’s the fun of science, making what seems impossible possible!
On that note: Cell Scientists… ASSEMBLE!
Have a friend who has Parkinson , has one or two year before needing a wheel chair. Are you that far in advance with your medication or stem cell Achievement. Can you help him.
Hi Mike,
I don’t work on Parkinson’s in my lab but the field is making some real progress overall. While I don’t think there’ll be a stem cell-related treatment in a few years, it’s possible in 5-10 years.