I’ve once again divided up the October edition of RMNU🔬 by trending research topic. Read on for remarkable placental science, new research involving in vivo genetic engineering, and more!
A photo of Marcella Townsend following treatment for severe facial burns using placenta-derived grafts. Credit: Kendrick Brinson/The New York Times/Redux
Trend of the month: Healing via placenta
Millions of placentas are discarded annually around the world. Given the regenerative medical potential demonstrated by placenta-derived tissue over the years, this is quite the unfortunate statistic. From preclinical data describing the regeneration of damaged hearts, to clinical trials targeting diabetic foot ulcers (here and here), and extensively documented use in ophthalmology, the list of current and potential applications is a long one. It’s especially useful that placenta-derived tissues are immunologically privileged, meaning they do not generate an immune response in patients, regardless of who the donor might have been.
This October, 47-year-old Marcella Townsend – who suffered second- and third-degree burns across more than 60 per cent of her body – shared her experience with placenta-derived grafts in the New York Times. In 2021, a propane explosion at her mother’s house left Ms. Townsend’s face, in her words, “unrecognizable.” You would never guess this looking at her today, however.
The biomaterial that was applied to her face had been manufactured from placentas donated by healthy, consenting women who delivered by elective C-section. Each donor sample is processed so that the amniotic membrane – that is, the layer facing the fetus – is peeled away and sterilized. The resulting material is then deep-frozen, dehydrated, or freeze-dried so that it’s ready for use. While burn treatment isn’t necessarily a new application for amniotic membranes, it’s still important to keep these stories in the spotlight given that these patients rely on donated tissues. There’s a ton of ongoing research on placenta-derived tissue – also out last month, see Nie et al.’s preclinical study investigating placental mesenchymal stem cells in modelled acute lung injury, and this human study by García-Vásquez et al. on amniotic membrane patches in retinal repair. I’ve written a separate, full-form blog on placentas in regenerative medicine for Signals so watch for it!
In vivo genetic engineering
Two big in vivo genetic medicine stories made headlines last month.
Before I launch into the main highlights, it’s worth noting that both protocols involved lipid nanoparticle (LNP) delivery systems. Perhaps you use these in the lab throughout your genetic engineering studies? If not, you’ve almost certainly benefitted from this technology. LNPs were used in COVID-19 vaccines to contain and deliver mRNA payloads to cells. It’s worth noting that LNPs are still the subject of much research to better understand how they interact with our bodies, despite generally being safe and well-tolerated in humans. Omo-Lamai et al.’s spring preprint is a great example of these ongoing efforts, in addition to this review from Nature Drug Discovery.
FDA-approved genetic technologies that involve DNA editing – such as Vertex’s Casgevy and Bluebird Bio’s Lyfgenia – were designed to be applied to cells in vitro before subsequent transplantation into patients. This is intended to minimize off-target edits and other side effects that might accompany in vivo gene editing. Of course, in vivo treatment could be simpler overall if executed safely, so it’s currently being investigated both clinically and preclinically. The goal is to deliver the corrective molecular machinery directly to the patient’s body, skipping that intermediate step.
You may have heard of Editas Medicine last December, when Vertex paid $100 million to license Editas’ Cas9 gene editing technology following a lengthy patent battle (and yes, that deal included Casgevy). Editas is back in the headlines again, as they’ve just announced preclinical results relevant to sickle cell disease (SCD) and beta-thalassemia. (Ed: read a personal account of thalassemia and treatments here.) Working on mice engrafted with their intended therapeutic target, human hematopoietic stem cells (HSCs), the team found that a single dose of targeted LNPs containing AsCas12a nucleases resulted in edits to 29 per cent of HSCs overall. Targeting the HBG1/2 promoter, these edits were designed to induce elevations in fetal hemoglobin, which modulates the severity of SCD by inhibiting the polymerization of adult sickle hemoglobin. To see the data, view their presentation here (you will have to register). There’s also another example of this approach published in the New England Journal of Medicine last August, but the editing in that case was done in vitro.
Also out this October, Gao et al. investigated in utero correction of neurodevelopmental conditions in rodents. First, they designed LNPs that degrade rapidly within cells and demonstrated reduced toxicity and immunogenicity in their studies. Using these custom LNPs, the authors first carried out a proof of concept experiment: Using Ai9 mice, they were able to deliver Cre mRNA to 30 per cent of cells in the developing fetal brain (on embryonic day 15.5). In this strain, Cre delivery results in the permanent expression of td-Tomato, a red fluorescent protein, in targeted cells. Following these animals through development, 60 per cent of hippocampal neurons and 40 per cent of cortical neurons had the edits (td-Tomato expression) by the time rodents were 10 weeks of age.
After completing this proof of concept, they shifted focus to Angelman syndrome, a neurodevelopmental disorder characterized by motor dysfunction, seizures, and severe cognitive impairment. The team successfully edited the target gene – this time using Cas9 mRNA and gRNA – in 21 per cent of the brain tissue (analyzed 10 days post-injection). This volume of edits could produce therapeutic benefits in practice, as editing at similar levels has been found to improve Angelman syndrome phenotypes in rodent studies involving postnatal injections. Furthermore, it’s not unreasonable to imagine that the earlier those edits are made, the more cells they’ll ultimately affect as division and growth proceed; the same percentage targeted earlier could have a greater impact overall.
Stem cells for central nervous system (CNS) regeneration
Patching macular holes and unlocking regulators of neural stem cell aging: The CNS has had quite a month.
The macula is a specialized retinal area responsible for central vision, allowing us to see high-definition details and colours directly in front of us. In rare cases, it can develop a small break, leading to blurring or distortion of a patient’s central field of view. This is called a macular hole, and it can either be caused by aging, as a complication from other eye diseases, or physical injury. While there are surgical treatments currently available for this condition, it can reoccur and treatment can be complicated in these cases (although interestingly, human amniotic membrane transplantation is listed as an option, depending on the circumstances – so it looks like we’ve come full circle). Iwama et al. investigated the option to treat this condition by transplanting human embryonic stem cell-derived retinal organoid sheets into Macaques with macular holes. Seven months after transplantation, the macular holes had successfully closed, as the grafts were found to both survive and mature into rods and cones. The fovea, which is right in the centre of the macula and creates the sharpest visual image, was found to be electrophysiologically active and overall vision did improve. However, further research will be required to investigate the extent of functional integration, as host-graft synaptic connections could not be confirmed. This might have resulted from protocol-related issues, including mild transplant rejection that was treated using steroid injections.
Next up, a newly developed CRISPR screen for regulators of neural stem cell (NSC) aging has produced interesting results. As we age, our quiescent NSCs activate at declining rates, which can be a detriment to memory, disease states, or injury recovery. Ruetz et al. have uncovered genes that, when knocked out, restore the activation of aged, quiescent NSCs. Starting from a group of 301 identified using a genome-wide screen on primary cell cultures, they found that their top genes involved glucose import and cilium organization. Taking the investigation in vivo, they further narrowed the pool to 24 genes. A top performer emerged as GLUT4, an insulin-sensitive glucose transporter. Indeed, knocking out Scl2a4 – the gene which codes for GLUT4 protein – gave in vivo neurogenesis a two-fold boost. Examining the functional implications of this, the authors found that aged NSCs demonstrated increased levels of GLUT4 expression and glucose uptake. Furthermore, knocking out GLUT4 or transiently starving the aged cells of glucose restored their ability to activate. However, this intervention did not affect young quiescent NSCs in the same way. The data thus suggest that an increase in glucose uptake could play a role in NSC decline over time, representing another major link between alterations to metabolism and aging.
Ruetz et al.’s work reminded me of previous findings relating dietary restriction to aging, which is not always a straightforward topic as exemplified by work in Nature a few weeks ago. I’m sure there will be much more data in the future to weave all these threads together. For now, it’s useful to keep in mind that GLUT4 is also integral to healthy functioning; read more on this here.
Additional recommendations
- Neural crest precursors from the skin are the primary source of directly reprogrammed neurons.
- Hot off the presses from my former thesis lab!
- Zinc finger nuclease-mediated gene editing in hematopoietic stem cells results in reactivation of fetal hemoglobin in sickle cell disease.
- Mesenchymal stromal cells as cancer promoters.
- This one’s a review, but given the subject matter, it’s a highly relevant read.
- FDA-Approved Phase II Stem Cell Treatment Trial Shows Significant and Diverse Improvements for Multiple Sclerosis (MS) Patients.
- One of the trial participants wrote a PopSugar article about her experience: I Participated in the First FDA-Approved Stem Cell Trial For MS. It Changed My Life.
- Do stem-cell transplants increase cancer risk? Long-lived recipients offer clues.
- Lots of conversation around cancer risk associated with CAR T, and this has somewhat reinvigorated media coverage of cancer risk associated with stem cell transplants due to all the comparisons being drawn between the two. The above article serves as a solid analysis of the following paper: Characterization of clonal dynamics using duplex sequencing in donor-recipient pairs decades after hematopoietic cell transplantation.
- Retrotransposons are co-opted to activate hematopoietic stem cells and erythropoiesis.
- Don’t skip this one: Following blood loss or during pregnancy, ancient viral DNA triggers the immune system in such a way that provides a boost of red blood cell production, helping to prevent anemia. The authors look at both rodents and humans in this study; really interesting work.
- Inflammation continues to be relevant as ever across fields: 1. Injured inflammatory environment overrides the TET2 shaped epigenetic landscape of pluripotent stem cell derived human neural stem cells; Inflammation impacts androgen receptor signaling in basal prostate stem cells through interleukin 1 receptor antagonist; 3. Dapagliflozin mitigates cellular stress and inflammation through PI3K/AKT pathway modulation in cardiomyocytes, aortic endothelial cells, and stem cell-derived β cells.
- Safety being seen in first 3 patients in stem cell therapy clinical trial.
- I reported on Aspen Neuroscience’s clinical trial investigating iPSCs for Parkinson’s disease back in May. At that point, only one person had received their new therapy the month before. The first real updates on safety are now coming through.
- Two interesting clinical trials are kicking off in Australia: 1. Clinical trial to test engineered skin for severe burns starts in Melbourne’s Alfred Hospital; and 2. Much-anticipated human trial aiming to repair spinal cord damage about to begin.
- Disease background influences fate of transplanted stem cells.
- Interesting coverage of this paper: Long-term lineage commitment in hematopoietic stem cell gene therapy.
- Delayed immune tolerance through donor haematopoietic stem cell infusion 14 months after kidney transplantation.
- SUMOylation of Warts kinase promotes neural stem cell reactivation.
- There was lots of buzz about this drosophila paper.
- Acquisition of durable insulin-producing cells from human adipose tissue-derived mesenchymal stem cells as a foundation for cell-based therapy of diabetes mellitus.
- A humanized monoclonal antibody targeting an ectonucleotidase rescues cardiac metabolism and heart function after myocardial infarction.
- Tuft cells act as regenerative stem cells in the human intestine.
- When senescence generates pluripotent stem cells.
- Age-associated imbalance in immune cell regeneration varies across individuals and arises from a distinct subset of stem cells.
- Targeting glioblastoma with a brain-penetrant drug that impairs brain tumor stem cells via NLE1-Notch1 complex.
- ISCT launches new resource on unproven cell & gene therapies.
- Differentiating visceral sensory ganglion organoids from induced pluripotent stem cells.
- Can Stem Cells Relieve Chronic Low Back Pain?
- Extreme autotomy and whole-body regeneration in photosynthetic sea slugs.
- An African perspective on genetically diverse human induced pluripotent stem cell lines.
- Cell and gene therapy investment ticks up after hard few years.
- Interaction between subventricular zone microglia and neural stem cells impacts the neurogenic response in a mouse model of cortical ischemic stroke.
- The effect of platelet-rich fibrin on the biological properties of urothelial cells.
- Mesenchymal stem cells with an enhanced antioxidant capacity integrate as smooth muscle cells in a model of diabetic detrusor underactivity.
- Unveiling the Immunomodulatory and regenerative potential of iPSC-derived mesenchymal stromal cells and their extracellular vesicles.
- Effective regulatory responses to predatory stem cell markets in Australia and Canada.
- Transcripts of repetitive DNA elements signal to block phagocytosis of hematopoietic stem cells.
- A prenatal skin atlas reveals immune regulation of human skin morphogenesis.
- SMAD3 mediates the specification of human induced pluripotent stem cell-derived epicardium into progenitors for the cardiac pericyte lineage.
- Stem cell studies detail how progenitor cells self-renew, differentiate and aggregate into early kidney structures.
- Judge Rules Against Stem Cell Clinic.
- Dynamically cultured, differentiated bovine adipose-derived stem cell spheroids as building blocks for biofabricating cultured fat.
- Surface tension enables induced pluripotent stem cell culture in commercially available hardware during spaceflight.
- Epicardial transplantation of antioxidant polyurethane scaffold based human amniotic epithelial stem cell patch for myocardial infarction treatment.
- YTHDC1-mediated microRNA maturation is essential for hematopoietic stem cells maintenance.
- Gladstone to present 2024 Ogawa-Yamanaka Stem Cell Prize to Neuroscientist Rusty Gage.
- A computational model reveals an early transient decrease in fiber cross-linking that unlocks adult regeneration.
- Immunomodulation by the combination of statin and matrix-bound nanovesicle enhances optic nerve regeneration.
- Distinct muscle regenerative capacity of human induced pluripotent stem cell-derived mesenchymal stromal cells in Ullrich congenital muscular dystrophy model mice.
- Amphix Bio obtains FDA breakthrough device status for bone regeneration product.
- Development of a quantitative prediction algorithm for human cord blood-derived CD34+ hematopoietic stem-progenitor cells using parametric and non-parametric machine learning models.
- Differentiation fate of a stem-like CD4 T cell controls immunity to cancer.
- Kaempferol enhances intestinal repair and inhibits the hyperproliferation of aging intestinal stem cells in Drosophila.
- Haploidentical hematopoietic stem cell transplantation for hematologic malignancies: a novel conditioning regimen with anti-T lymphocyte immunoglobulin instead of anti-thymocyte globulin for in vivo T cell depletion.
- Nutrient-sensing alteration leads to age-associated distortion of intestinal stem cell differentiating direction.
- Single-layer graphene oxide nanosheets induce proliferation and Osteogenesis of single-cell hBMSCs encapsulated in Alginate Microgels.
- Differentiation fate of a stem-like CD4 T cell controls immunity to cancer.
- Increased cholesterol synthesis drives neurotoxicity in patient stem cell-derived model of multiple sclerosis.
- Joe Rogan shows more love for unproven stem cells despite risks.
- Maryland biotech gets green light for stem cell-derived therapy for diabetes, aiming to compete with Vertex.
- FDA names stem cell therapy for FA, PPL-001, rare pediatric disease.
Lyla El-Fayomi
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