√ Can We Grow New Brain Cells As 4Dukts? It Depends On Who You Ask

Can we humans grow healthy new brain cells as 4dukts?

The answer to this question is a big deal because it could have major impact on aging. Those hoped-for new brain cells could keep our brains functionally younger. Who doesn’t want to slow down the aging of their brain, right? Slowing down aging of the brain via new cell growth more broadly would have major impacts on society.

Cell Stem Cell Boldrini, et al., 2018, Part of Figure 1

Researchers have gone back and forth on this over years.

Fairly long ago, it was thought the answer was definitely “No, we humans can’t grow new brain cells”, but in the last few decades a loose consensus has emerged that in fact the answer is, “Yes, to some degree.”

A recent Nature paper, however, said “No” again. It challenged that “Yes” by directly arguing we don’t make new brain cells. Neuroscientists who study this stuff generally reacted skeptically. The paper’s title was, “Human hippocampal neurogenesis drops sharply in children to undetectable levels in 4dukts.”

Yet an even newer paper,this time in Cell Stem Cell that is Boldrini, et al. argues “Yes” and goes further to say, in fact, that we 4dukts and even older 4dukts can grow brain cells just about as well as the younger folks. This paper’s title pretty much directly contradicts the above one as it says, “Human Hippocampal Neurogenesis Persists throughout Aging.”

So who’s right and who’s wrong?

My gut feeling is that there is 4dukt human neurogenesis and there are stem cell populations in 4dukts and even fairly aged humans.

It’s really hard to conclusively prove a negative thing in science like the claim that there’s no neurogenesis in 4dukt brains. I bet the team recently arguing no detectable new neurogenesis used methods that simply didn’t detect it. It’s much harder to dismiss the findings in the newer paper (and in many past ones) showing 4dukt human hippocampal neurogenesis and the presence of stem/precursor cells. See part of Boldrini Figure 1 above showing evidence of neural progenitor/stem cells in the 4dukt brain. The data in that paper are clear.

Still, this new paper arguing for sizable levels of stem cell activity in the 4dukt human brain found some effects of aging on the brain and that neural precursor numbers in older 4dukts are somewhat lower than say teenagers.

People are more generally really wanting their brains to stay robust as they age. I’ve covered brain aging in the past on this blog and efforts to counteract it, mainly via stem cell-related efforts such as exosomes, which were the focus of a paper I was fairly skeptical about some months back. Some people also think that stem cell transplants or infusions of young blood might fight brain aging, but those are somewhat wilder ideas.

I’m hopeful that there are real ways eventually found to keep our brains healthy and even producing more new, healthy cells and stem cells as we add on the decades. The debate over 4dukt human brain stem cells might continue in years to come, but most people I know think there is some neurogenesis going on even as we age, which provides hope for the aging human brain.

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√ Weekend Reads: Reversing Death Of Pig Brain Cells, Brain-Gut Stem Cell Link, Plant Stem Cells, More

Untreated pig brain at left shows lots of death and few neurons (green) hours after death, but the image on the right shows a brain connected to a system called BrainEx that Yale researchers report kept more neurons alive. Source.
Stefano G. Daniele and Zvonimir Vrselja, Sestan Laboratory, Yale School of Medicine

It’s been a cool week for stem cell and other associated kinds of research. In this post I have a series of links to a variety of interesting developments and papers.

Gene therapy cures bubble boy infants. William Wan over at the WaPo on this good news. Nope, this wasn’t done with CRISPR, but rather with a viral transgene approach (not TALENs as I mistakenly had originally written here).

“The pigs were dead. But four hours later, scientists restored cellular functions in their brains”. This reminds me of a post I did on a biotech claiming oddly to reverse death of human brain cells at least in part with a laser. In this new report, Yale researchers have a system called BrainEx that purportedly keeps brain cells alive for hours. Note in the image at left that the untreated brain is 8 hours post-death while the image of treated brain is only four hours after death. Still, it seems like a striking difference, but I can’t help but feel a bit skeptical about how much meaning this report really has. We’ll see.

“Researchers discover crucial link between brain and gut stem cells”. The gut is very tied to overall health in many ways and was also recently found to be a novel reservoir of hematopoietic stem cells in people too.

“To protect stem cells, plants have diverse genetic backup plans.” Yes, plants have stem cells and they aren’t just made by nature to go into sketchy anti-aging “cremes”.

Kind of a first-person piece in the NYT, “The Lifesaving Power in Stem Cells” on cord blood by Susan Gubar. It has this in your face kind of subtitle in reference to stem cell clinics, “Liars and thieves should not be allowed to detract from legitimate scientific research that has made umbilical cord blood mystic in its regenerative powers.”

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√ Probing Nature Pub’S Puzzling Claim Of Brain Cells Globetrotting Into Prostate Tumors

Mauffrey, et al., Nature 2019 Fig 3c-e. Yellow cells are reported to be brain neural cells invading prostate tumor.

A new Nature paper makes the striking claim that neural precursor cells of the brain migrate all the way to prostate tumors. Furthermore, the team led by Claire Magnon claims that these long-distance cellular travelers from the brain not only take up residence in the prostate but also strongly drive progression of the prostate cancer via neurogenesis there.

From what I know, this claim goes counter to general principles of animal physiology so if it’s accurate, it’s a huge deal. Other than blood cells, most cells in certain tissues don’t just wander far off to other distant tissues even in disease states. Still, in science we need to challenge general assumptions and cells do sometimes wander.

The paper, Mauffrey, et al., entitled “Progenitors from the central nervous system drive neurogenesis in cancer”, is mostly based on a mouse model of prostate cancer. The tumors are driven in these mice by exogenous Myc, although the team also analyzed some human prostate tumor samples in correlative work.

The claim of neural precursors globe-trotting from the brain to prostate is not addressed in the human context, but the authors seem to think it also occurs there. Since most of the paper is on mice, we need to invoke #inmice here somewhat. If true in humans too, this is an even bigger discovery.

As a Myc, cancer, and stem cell researcher, this paper caught my attention. I also am a prostate cancer survivor myself.

I’m somewhat skeptical of the claims here and I think that the authors went out on a limb with how strongly they made their claims. In particular I strongly doubt that this occurs as part of the normal disease process in human prostate cancer development. It’s not that I see any technical red flags on first glance in the pub, but rather the core claim just doesn’t make sense to me. Of course, that doesn’t mean it’s wrong, but I’m surprised it hasn’t made more press.

So what’s going on here?

The paper largely relies on the assumption that a marker of central nervous system (CNS) precursor cells called DCX definitively marks only these CNS cells. Thus, when the authors see DCX+ cells inside prostate cancers (which is convincing), they claim that they must come from brain. However, for me a much simpler explanation is that instead local cells take on a DCX+ fate or perhaps a few already have it such as in a prostatic nerve fiber (note that DCX+ cells are found in the peripheral nervous system too) and are attracted into the tumor locally. I don’t know that the paper rules out these simpler possibilities so that’s a concern.

Even so, let’s say the paper is right that the prostatic tumor DCX+ cells are from the brain, how would brain cells get all the way from the brain to the prostate? That’s like going from Earth to the Moon, in cellular terms. The authors can detect a few DCX+ cells in the blood of their prostate cancer mice, but not many. Still, they argue that the cells go through the blood-brain barrier (on its own, a big hurdle) and then all the way from brain to prostate cancer in the vasculature. That’s possible, but surprising.

If this does happen in people, when do the brain precursor cells go to the prostate relative to the tumor initiation and growth? If the brain cells go there prior to tumor initiation, then why do they even go there in the first place? If as seems more likely they go later, perhaps attracted by the tumor, how do they contribute to the progression of the already existing tumor? The authors argue the brain cells definitely contribute to the tumor’s progression. They also suggest brain cells go to other kinds of tumors, at least in mice.

This is one of those papers that strongly shakes things up. I saw an accompanying News & Views piece focused on it, but unfortunately it doesn’t really discuss limitations of the work or ask probing questions.

In a way, I hope I’m wrong in being so skeptical. The new finding, if replicated and more definitively proven, would be very cool and I like it when there are paradigm-challenging or breaking discoveries. Still, for me at least, it’s going to take a lot more proof to be convinced.

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