“Regenerative medicine news under the microscope” is a monthly feature highlighting big stories in stem cell research. I will sample the latest and greatest findings in recent press and package them into a single post.
July was another great month in regenerative medicine research news. In this edition, I cover the first true case of in vitro gametogenesis, the molecular mechanisms of liver regeneration, a compassionate use stem cell study for muscular dystrophy, and more!
I’m also excited to introduce a new element to this monthly feature – Pick of the Month. At the end of the year, I’ll remind you of my picks and you (our fantastic readers) will vote for your favourite – Reader’s Pick!
Healthy adult mice grown from fertilized ‘ovarioids.’ From [T. Yoshino et al., Science 373, eabe0237 (2021). DOI: 10.1126/science.abe0237]. Reprinted with permission from AAAS.
A significant field-first: In vitro gametogenesis
Prior to this month, the only way to produce female gametes outside of the body was by incubating a stem-cell-derived primordial egg cell with harvested tissue from an animal’s reproductive organ – the ovary. That has changed, thanks to this work, published in Science.
Yes, that’s right, it’s another “-oid.”
The “ovarioid,” derived from stem cells, provides the niche necessary for oocytes to grow and mature into eggs in vitro. The authors fertilized some of them to prove they were functional, and healthy newborn mice were born.
The significance of this work is that a few decades in the future, this technology might help women who have, for whatever reason, lost reproductive function. They could have eggs grown in a lab with their own genetic material. It could also help couples in the LGBTQIA2S+ community produce children who share their genetics.
Of course, whenever a new technology is developed with the power to create or edit a life, ethical concerns are raised. More on that here.
SARS-CoV-2 and the central nervous system: Another new organoid model
It seems we’re quickly approaching a point where we’ll have a full fleet of in vitro systems we can use to examine the effects of COVID-19 on our physiology. I’ve talked about many of these in previous blogs.
The latest addition is the neural-perivascular assembloid, which was developed to determine how exactly the virus is able to cross the blood-brain barrier (BBB) to trigger ischemic strokes, seizures, hemorrhaging, and much more. All in all, central nervous system (CNS) symptoms present in up to 85% of intensive care unit patients.
Human neurons themselves are not susceptible to infection by SARS-CoV-2, so another cell type needed to be identified; the “Trojan horse,” identified in Nature Medicine this month, turned out to be pericytes.
Assembloids are essentially cortical organoids with pericytes introduced into the system, making for a more sophisticated model. These cells wrap around the blood vessel and are vulnerable to infection due to expression of the ACE2 receptor. They’re positioned such that they form an interface between the blood vessel and astrocytes, which have been found to be susceptible as well. Pericytes serve to form a connection between neighboring cells, plus coordinate and regulate signaling critical for CNS functions including BBB permeability and neuroinflammation.
Another possibility is that infection of these cells may lead to inflammation of the blood vessels, which in turn may result in clotting, stroke, or hemorrhaging.
Next steps include attempts to develop assembloids which include blood vessels to produce a more accurate model.
Liver regeneration: Cracking a two-thousand-year-old mystery
The liver’s regenerative properties have been known to us since ancient times (see: The ancient Greek myth of Prometheus). It’s the only organ that can be cut down to one third of its size and still grow back. It’s a remarkable capability that has been the subject of investigation for years, mostly because it could hold the key to human regeneration more broadly.
This month, we finally have some answers on the matter, and it isn’t a totally unexpected result: The key seems to have been in the epigenetic code all along.
Researchers at NYU Abu Dhabi found that while the liver was in a state of quiescence, an epigenetic mark that represses the expression of certain proliferation-related genes was present (H3K27me3, a tri-methylation of histone H3 on lysine residue 27). However, when the liver is regenerating, this repressive epigenetic mark is removed from these particular gene promoters, facilitating expression.
The authors of the study suggest that in order to manipulate this system, more work will be required, but this is a strong step in the right direction.
Compassionate-use study reveals utility of mesenchymal stem cell treatments in alleviating symptoms of muscular dystrophy
Muscular dystrophies – muscle wasting diseases that result from genetic mutations – can result in death by cardiomyopathy or respiratory failure. Current options range from supportive care to drugs, including steroids, and can have adverse side effects including bone fractures and weight gain.
The patients at the centre of the study, published in STEM CELLS Translational Medicine, had varying types of muscular dystrophies, and the number of mesenchymal stem cell (MSC) injections they received were not quite consistent across cases, ranging from 1-5 per treatment course. Treatment courses could be repeated up to twice every two months.
Muscle strength assessments pointed to significant improvements in several parts of the body, including the limbs, hips, elbows and shoulders. In fact, their most successful case was a patient who no longer needed a crutch or rehabilitation, and who returned to work full-time. Also, no side effects were observed, which is always encouraging.
It’s too early to say where these findings place MSCs as a treatment. Outstanding questions surround the duration of the therapeutic effects, the optimal treatment scheme, and how to balance this option with existing treatments such as drugs and rehabilitation.
Stem cell self-defense against viral assault
Differentiated mammalian cells primarily rely on the interferon system to defend against a viral infection. Interferons are cytokines secreted when a virus is detected, and which induce the expression of hundreds of genes, ultimately blocking viral replication across multiple levels.
In contrast, worms and insects rely on an enzyme called Dicer, which is part of an RNA interference (RNAi)-based system.
In this study, Poirier et al. reveal that mammalian stem cells, like worms and insects, employ a Dicer isoform called aviD (antiviral Dicer), which slices viral RNA into small interfering RNAs. These are subsequently used to cleave homologous viral RNAs in a sequence-specific manner.
As proof of principle, the authors found that the aviD system is a successful protective measure taken by stem cells against SARS-CoV-2 and Zika virus. This new knowledge could be useful in the ongoing search for effective and safe antiviral therapies. If mammalian stem cells employ this system, might it one day be safe enough to deploy in clinical settings to treat viral infections? For more on the prospect of RNAi-based treatments, check out this review article by Uludağ et al. in Frontiers in Bioengineering and Biotechnology.
Additional recommendations
Here are some papers/headlines that I didn’t have room for above:
Single-cell analysis enters the multiomics age. Jeffrey M. Perkel in Nature.
First immunohistochemical evidence of human tendon repair following stem cell injection: A case report and review of literature. Alt et al. in World Journal of Stem Cells.
Identifying the genes responsible for driving mature cells back to regenerative states: ATF3 induces RAB7 to govern autodegradation in paligenosis, a conserved cell plasticity program. Radyk et al. in EMBO Reports.
Development of a quantitative prediction algorithm for target organ-specific similarity of human pluripotent stem cell-derived organoids and cells. Lee et al. in Nature Communications.
A DNA-repair pathway can affect transcriptional noise to promote cell fate transitions. Desai et al. in Science.
Engineered Cells Successfully Treat Cardiovascular and Pulmonary Disease. Elizabeth Fernandez for UCSF News.
Chemotherapy-induced transposable elements activate MDA5 to enhance haematopoietic regeneration. Clapes et al. in Nature Cell Biology.
Hematopoietic stem cell transplant for erythropoietic porphyrias in pediatric patients. Wang et al. in Pediatric Blood & Cancer.
FDA Gives Green Light for Multiple Sclerosis Stem Cell Trial. Business Wire.
Improved hematopoietic stem cell transplantation upon inhibition of natural killer cell-derived interferon-gamma. de Figueiredo‐Pontes et al. in Stem Cell Reports.
Stay tuned for my next post, coming up in August!
Lyla El-Fayomi
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