“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.
This month, we open up the voting for “Reader’s Choice 2021.” A week from today, we’ll list select research stories from each blog post in this series (most of these will be Picks of the Month), and it’s up to you to pick the one that inspired you the most. Voting will close on December 31st, and the winner will be announced in January.
In this edition, I cover a fascinating leap forward in spinal cord injury repair, the latest in COVID-related organoid research and more!
Pick of the Month
Credit: Samuel I. Stupp Laboratory/Northwestern University via SciTechDaily
Paralyzed mice walk again thanks to reparative “dancing” molecules
The video is stunning. A mouse (above right) shuffles towards a researcher, sluggishly putting one hindpaw ahead of the other, in eager pursuit of an object. Looking at the little guy, it’s hard to imagine that this mouse had a spinal cord injury that eliminated any and all movement in its hind limbs, and that this injury had been largely healed following treatment with a sophisticated new injectable therapy. In the original video on YouTube (above left), you’ll also see an untreated paraplegic mouse that can only pull itself forward using its forepaws, highlighting just how significant the movements in the clip above truly are.
When I think of “regenerative medicine,” restoring movement to paralyzed individuals comes to mind as one of our ultimate goals in the field. This month in Science, Álvarez et al. do just this in rodent models of severe spinal cord injury.
What sets their molecularly complex treatment apart? They engineered short, modified peptides that promote axon regeneration, cell proliferation and blood vessel formation – but most importantly, the peptides are designed to remain on the move. This makes contact with receptors in the tissue more likely, because the receptors are moving around in the membrane as well. The treatment is a liquid when injected into the spinal cord, but when it comes into contact with the body, a hydrogel is formed that mimics the spinal cord’s extracellular matrix. That being said, the molecules themselves are contained within a nanofiber network, and yet they’re able to move around within it. This novel approach, described by the authors as a “supramolecular peptide fibril scaffold,” was the key to their success.
Mice were able to achieve functional recovery four weeks after a single injection; the reason is that the treatment stimulated: 1) the regeneration of severed axons in the spine; 2) re-formation of the myelin sheath around neurons; 3) growth of blood vessels in the injury site; 4) better motor neuron survival; and, 5) reduced scar tissue formation.
The icing on the cake? The treatment is biodegradable, breaking down into nutrients for the patient’s cells within 12 weeks and then disappearing.
In early 2022, the authors will be approaching the Food and Drug Administration to request permission for human trials.
Gastric organoids recruited in the fight to understand COVID-19
As discussed in one of my previous blogs, COVID-19 patients often present with gastrointestinal (GI) symptoms. There is evidence suggesting that SARS-CoV-2 can replicate in the GI tract, and persist in this region of the body even after viral shedding from the respiratory tract has ceased. In addition to this, the virus can be detected in stool samples and indeed air samples collected from patients’ toilet areas. If you’re interested in reading more about the risk of COVID-19 transmission in public washrooms, research out of Australia this month has you covered.
Another disturbing fact that is important to this story is ACE2 receptors, which the virus binds to, are present in the mouth. Taken together, these findings are fueling new investigations into fecal-oral SARS-CoV-2 transmission (I apologize if you’re reading this at lunch time).
The stomach would, of course, be a critical stop on the way to the intestines. In this Nature Communications paper, researchers employ gastric organoid systems derived from both adult and fetal cells to examine the ability of SARS-CoV-2 to achieve infection across different developmental stages. To specifically study the gastric epithelium, they reversed the polarity of the organoid, turning it inside-out. They found that both pediatric and late-fetal organoids were susceptible, whereas developmentally younger organoids were less so. Also, adult gastric organoids were more vulnerable to infection following differentiation.
In summary, they report that it is indeed possible for the virus to efficiently infect the gastric epithelium, pointing to a potential role in fecal-oral transmission of COVID-19. If you’re wondering whether or not the virus can survive stomach acids to be able to achieve infection of gastric epithelium, check out this paper. So far, the answer seems to be yes, depending on the pH of your stomach acid.
Mesenchymal stromal cells are just dying to help
Mesenchymal stromal cells (MSCs), also known as mesenchymal stem cells, have been featured in this series before (here and here). They’ve been found to be useful in the treatment of multiple diseases in preclinical models. However, work to elucidate the specific molecular mechanisms underlying their therapeutic action has been ongoing, as the cells tend not to survive infusion, yet are still effective.
This month, Pang et al. reveal the details behind a downright Shakespearean piece of the puzzle: the therapeutic value of MSCs lies not in their life, per se, but in their death. Prior to this study, MSC apoptosis – the process by which cells die in a controlled manner – had been linked to the stem cells’ mechanism of action in improving conditions including sepsis, acute lung injury, airway inflammation caused by allergies, and graft-versus-host disease. However, little evidence existed to confirm whether or not it was the host’s response to dying MSCs that was the key… until now.
Apoptotic cells have been found to release anti-inflammatory or therapeutic signals that serve to regulate their own death in such a way that does not damage surrounding tissue. It turns out that these properties can also modulate different aspects of host immune function to reduce disease severity.
In this study, the authors investigated MSC apoptosis by impairing it, and saw a clear reduction in their immunomodulatory properties in models of lung inflammation and multiple sclerosis. They further reveal that engulfment by host immune cells also plays a role in their therapeutic action, showing that macrophages that apoptotic MSCs take on sustained alterations in their function and immunometabolism. Ultimately, these altered macrophages go on to fight inflammation in a way that’s of significant clinical interest.
Good things in small packages: Stem cell potential linked to size
It’s known that senescent cells, which have gradually lost their regenerative potential with age and exposure to various damaging factors, are larger than younger, healthier cells. However, prior to this month, it was not known whether or not cell enlargement could drive senescence and functional decline in a causative direction.
Lengefeld et al. asked this question, and found that preventing hematopoietic stem cell (HSC) enlargement by affecting the biosynthesis of macromolecules, or reducing HSC size by speeding up the cell’s progression through a phase of the cell cycle critical for cell growth, actually prevents the loss of HSC potential.
The authors propose an interesting model: As stem cells proliferate and age, they accumulate DNA damage. This damage, when detected by the cell, triggers a temporary time-out from division to conduct repairs. During these time-outs, however, the cells continue to grow, increasing in size. These size increases, in turn, cause proliferation defects. Check this paper out in Science Advances.
Additional recommendations
Here are some papers/headlines that I didn’t have room for above:
A Cure for Type 1 Diabetes? For One Man, It Seems to Have Worked. Gina Kolata for The New York Times. |AND| Breakthrough within reach for diabetes scientist and patients nearest to his heart. Clea Simon for The Harvard Gazette.
Stem cells expand potency and alter tissue fitness by accumulating diverse epigenetic memories. Gonzales et al. in Science.
Long-term repair of porcine articular cartilage using cryopreservable, clinically compatible human embryonic stem cell-derived chondrocytes. Petrigliano et al. in npj Regenerative Medicine.
The cardiomyocyte disrupts pyrimidine biosynthesis in non-myocytes to regulate heart repair. Li et al. in Journal of Clinical Investigation.
Combination of human endothelial colony-forming cells and mesenchymal stromal cells exert neuroprotective effects in the growth-restricted newborn. Chand et al. in npj Regenerative Medicine.
Generation of functional ciliated cholangiocytes from human pluripotent stem cells. Ogawa et al. in Nature Communications.
How the overlap between artificial intelligence and stem cell research is producing exciting results. Annie Brown for Forbes.
A library of induced pluripotent stem cells from clinically well-characterized, diverse healthy human individuals. Schaniel et al. in Stem Cell Reports.
A possible sterilizing cure of HIV-1 infection without stem cell transplantation. Turk et al. in Annals of Internal Medicine.
Large-scale integration of single-cell transcriptomic data captures transitional progenitor states in mouse skeletal muscle regeneration. McKellar et al. in Communications Biology.
Lots of spiny mouse work this month! – Spiny mice activate unique transcriptional programs after severe kidney injury regenerating organ function without fibrosis. Okamura et al. in iScience. |AND| Ischemic tolerance and cardiac repair in the spiny mouse (Acomys). Koopmans et al. in npj Regenerative Medicine. |AND| Adult spiny mice (Acomys) exhibit endogenous cardiac recovery in response to myocardial infarction. Peng et al. in npj Regenerative Medicine.
NRG1/ErbB signalling controls the dialogue between macrophages and neural crest-derived cells during zebrafish fin regeneration. Laplace-Builhé et al. in Nature Communications.
The American stem cell sell in 2021: U.S. businesses selling unlicensed and unproven stem cell interventions. Leigh Turner for Cell Stem Cell.
Antibody-drug conjugates plus Janus kinase inhibitors enable MHC-mismatched allogeneic hematopoietic stem cell transplantation. Persaud et al. in Journal of Clinical Investigation.
NR2F2 controls malignant squamous cell carcinoma state by promoting stemness and invasion and repressing differentiation. Mauri et al. in Nature Cancer.
Cis-regulatory architecture of human ESC-derived hypothalamic neuron differentiation aids in variant-to-gene mapping of relevant complex traits. Pahl et al. in Nature Communications.
Development of allogeneic HSC-engineered iNKT cells for off-the-shelf cancer immunotherapy. Li et al. in Cell Reports Medicine.
The CRISPR children. Vivien Marx for Nature Biotechnology.
Synthetic dynamic hydrogels promote degradation-independent in vitro organogenesis. Chrisnandy et al. in Nature Materials.
Human adipose-derived stromal/stem cells expressing doublecortin improve cartilage repair in rabbits and monkeys. Ge et al. in npj Regenerative Medicine.
Stay tuned for my next post, coming up in January! And watch for the “Pick of the Month” considerations in December.
Lyla El-Fayomi
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