April and May are incredibly busy months for me. This is when all of our major scientific meetings happen. At the end of April is the Experimental Biology meeting. There, I get to get my geek on and learn about new and exciting physiology, but really from a “basic science” perspective. (I put “basic science” in scare quotes, because I think it’s not a relevant term in physiology, especially given how many of are doing applied research. Still, my clinician friends love it, so onward we march.) Then, at the beginning of May I attend the Pediatric Academic Societies(PAS) meeting. This meeting tends to be more clinically-oriented, with focuses on model-based research, patient population research, and clinical practice. I like this mix and I almost always leave with more questions than I could ever answer in a lifetime.
I’m at PAS now and one of the major themes, as it was last year, is stem cell therapy to treat pediatric diseases. Diseases like bronchopulmonary dysplasia, type 1 diabetes, acute respiratory distress syndrome in the intensive care unit, etc. One of the statements that I’ve heard repeatedly is that stem cells traffic to the damaged/affected/diseased tissue, do that thing they do, someone usually says “inflammation”, and then the cells “disappear.” Some of the theories commonly thrown around are that they either differentiate or undergo apoptosis when their work is done (a programmed cell death).
That would be very noble of those little cells, either fading away into the background or throwing themselves on their proverbial caspase swords after their the job is done. Wouldn’t it?
(Image and quote sources here, here and here)
I don’t think it’s that simple and, every time I hear someone suggest that stem cells just “go away”, I want to grab them and yell, “BUT HAVEN’T YOU SEEN THIS???!?! OMFG, IT’S THE MOST AMAZING THING I’VE EVER SEEN! EVER!!1!!11!!!!ELEVENTY!1!”
The “THIS” I refer to is work done by my colleague, respiratory physiologist Dr. Jahar Bhattacharya and his group at Columbia University. At the last two Experimental Biology meetings, Jahar presented his findings that the reparative prowess of bone marrow derived stromal cells comes from their ability to transfer their mitochondria. That is, in a mouse model of experimentally-induced lung injury, BMSCs create channels to the damaged alveolar epithelium and send their mitochondria over to repair the injury. The mitochondria transfer restores the normal metabolic function of the damaged cell. To demonstrate this, the group stained the cells green and mitochondria red. Then, using intravital microscopy, the group observed the transfer of mitochondria between the BMSCs and alveoli and the associated increase in ATP production.
This is part of Figure 1 from the paper. Note the cells in green and mitochondria in red. License for non-profit use granted by Nature Publishing Group.
As I mentioned, I’ve heard Jahar speak about this work on a couple of occasions. Most recently, he showed video of the mitochondrial transfer during a banquet in which he was talking about serendipity in science. It’s still the coolest damned thing I have ever seen. He noted that his group only noted this phenomenon because they had originally grown their BMSCs too densely. When they examined the cells, they found all of these projections. Each time I’ve heard about his work, I have wondered what other organelles these cells might be transferring.
I think this organellar transfer hypothesis might be important in explaining some inconsistent results in the literature. In a paper last year in Pediatrics Research, Sutsko, et al. examined the efficacy of MSCs versus their growth media in a rat model of bronchopulmonary dysplasia, also called chronic lung disease of prematurity. Several groups have investigated the use of growth media because 1) it seems to be at least partially efficacious and 2) people are still concerned about the long-term safety of stem cell injection. Especially in the lung. These authors followed the rats for 100 days after treatment and found that both media and MSCs improved lung development, but the MSCs were more effective. They tracked MSCs engraftment by instilling MSCs whose nuclear DNA had been transfected with green fluorescent protein (GFP, or that stuff that people use to make glow-in-the-dark sheep). This should cause the MSCs to make GFP and glow green. They instilled the stem cells into the trachea and, after 100 days, stained for GFP and found little remaining fluorescent signal. These authors concluded that the cells had not engrafted into the lung and, thus, the cells and media must be working by releasing mediators (a so-called paracrine mechanism). This puzzled me though. What mediators would the cells release that wouldn’t be in the media? Perhaps, as Jahar’s work would suggest, the effects aren’t paracrine at all. Perhaps in this case the MSCs were more effective because they could transfer their mitochondria. Because the GFP gene wouldn’t be in the mitochondrial DNA, they’d never find them using this technique.
I offer the caveat, though, that this is all probably pretty speculative.
So, where have all the stem cells gone? And how do they repair damaged tissue? I have a feeling the answer is even more amazing than we think…