“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, I cover a technologically advanced exploration of cranial microvasculature, iPSC-based advances in schizophrenia research, the latest on stem cells in the fight against COVID-19, and more!
Pick of the Month
Quantitative 3D-imaging platform for the cranial microvascular environment: Visualization at single-cell resolution
The dynamic spatial interaction between blood vessels and osteoprogenitors during critical processes, including the growth of craniofacial bone, its healing processes, and remodeling, posed a serious knowledge gap prior to this month. An understanding of these physiological phenomena will contribute to the development of treatments for vascular abnormalities in craniofacial bone, which have been linked to syndromes including cleft palate, craniosynostosis (aberrantly early closure of skull sutures that, in its most severe forms, can lead to physical deformities, visual/sleeping impairments, headaches and developmental delays), mandibular hypoplasia (underdevelopment of the lower jaw), and more. In future, advanced regenerative medicine solutions for both congenital conditions and injuries will greatly benefit from, and will be informed by, research into the craniofacial regenerative niche and its healing processes.
Historically, older imaging technologies have limited the amount of information we’ve been able to collect in this field, but researchers have capitalized on a combination of newer technologies to overcome these limitations. Using whole-mount immunostaining, optical tissue clearing, light-sheet microscopy, and 3D image analysis, Rindone et al. built maps of vessel subtypes and skeletal progenitors in frontoparietal bones at single-cell resolution. They then used this technology to show how the spatial distribution of these elements vary during growth, remodeling and healing. In addition, the authors emphasize that this technology can be extended to study other cell types not explored here, such as neurons and immune cells, highlighting that this is truly the beginning of a series of investigations that wouldn’t have been possible in previous years.
The video shows 3D light-sheet microscopy revealing the distribution of different blood vessel phenotypes and skeletal progenitors in the murine calvarium at single-cell resolution. Credit: Rindone et al. 2021
Using iPSCs to advance our understanding of schizophrenia on two separate fronts
Research stories at the intersection of stem cells and psychiatry are among my favourite to read about. This month, the field has advanced in its efforts to understand and treat schizophrenia on two fronts. Both studies I’ll highlight use induced pluripotent stem cell (iPSC) technologies to model the disease, but two different cell types were studied – neurons in the first and glia in the second.
Schizophrenia is a brain disorder that is defined by delusions, hallucinations, cognitive difficulties and negative symptoms in the sense that certain functional abilities become diminished (including blunted emotions, motivations, and other depression-like symptoms). Diagnoses are typically made as early as the teenage years through to a patient’s early thirties.
Though schizophrenia can be successfully managed with treatment there is no cure, and so our efforts to understand the root cause of the disorder are ongoing.
In the first study I’m covering, Yamamoto et al. generated patient iPSCs, reprogrammed them to neurons, and identified multiple alterations in molecular and cellular phenotypes. They observed increased glutamatergic (excitatory) neurotransmission, higher AMPA receptor expression and synaptic densities, and altered D2 (dopamine) receptor mRNA splicing. They also conducted whole-exome sequencing, allowing them to pin down specific genetic factors contributing to these abnormalities. Though the authors do mention that this work should be further confirmed in larger sample sizes, they also discuss the fact that schizophrenia is a clinically heterogeneous disease, meaning the specific molecular and cellular pathologies may vary across patients. Therefore, the iPSC-based approach they’ve taken here is a step in the direction of personalized medicine for the psychiatric condition.
The second study in question examines the role of astroglia (a class of neural cells) in the pathophysiology of schizophrenia. Using both healthy and patient-derived iPSCs, Szabo et al. investigated temporal patterns of astrocyte differentiation during stages of development previously shown to be critical in the etiology of the disease. Through RNA sequencing, the authors were able to identify novel transcriptional dynamics in combination with associated functional changes, including altered calcium signaling, decreased glutamate uptake, and more.
For more on the use of iPSCs in psychiatric research, check out this recent review (published just last month) in Biological Psychiatry.
Stem cell research continues to advance our understanding of COVID-19, plus offer potential treatments
This highlight is another double-feature.
You’ve probably heard about mesenchymal stem cell (MSC) treatments and their potential to improve the symptoms of COVID-19 in various clinical trials to date (see this interesting ethical perspective piece in Stem Cell Reports, out this month, on how such research is also being abused). Zhu et al. reveal how exactly mesenchymal stem cells may be working in the body to produce these improvements in their Phase II clinical trial findings, pointing to multiple immunomodulatory mechanisms underlying MSC-based treatment efficacy.
Another informative COVID-19 story out this month investigated the audiovestibular symptoms experienced by many COVID-19 patients since the beginning of the pandemic. These symptoms include hearing loss, vestibular dysfunction and tinnitus. The question was, are the effects of SARS-CoV-2 on this sensory system direct – meaning the virus is directly infecting cells of the inner ear – or indirect, via the immune system? Exploring 10 patient cases in combination with in vitro investigations, the authors report that not only does inner ear tissue express the angiotensin-converting enzyme 2 receptor found to be targeted by SARS-CoV-2 plus other molecular components required for viral entry into the cells, but also that human hair and Schwann cells in vestibular tissue can indeed be infected by the virus. They also introduce three human iPSC-based in vitro models to study inner ear infections: 2D cultures of otic prosensory cells (that give rise to auditory and vestibular hair cells in developing organisms) and Schwann cell precursors, plus 3D inner ear organoids. Ultimately, this study sheds light on the mechanisms underlying the audiovestibular symptoms reported by COVID-19 patients, plus offers new in vitro models for future investigations.
ICYMI, here’s a detailed review released last month covering how human iPSC-based organoid systems have advanced COVID-19 research.
Gene therapy administered to children for ADA-SCID remains effective 11 years later
Adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) is a genetic condition that makes exposure to germs potentially fatal for babies with the disease. If left untreated, these babies often pass away within their first two years of life due to a mutated ADA gene, critical for proper functioning of the immune system.
Fortunately a Phase II clinical trial, led by Dr. Donal Kohn, offers a potential cure for the condition in the form of a genetic therapy. The treatment involves the removal of blood-forming stem cells from each child, the delivery of the healthy ADA gene to these cells in vitro, and the replacement of the stem cells back into the child’s bone marrow. Of the 10 children who received the treatment nine remain stable, indicating that the therapy was not only effective, but that it continues to be effective in the long term. Though not yet cleared by the U.S. Food and Drug Administration (FDA), this gene therapy is a significant improvement over other treatment options. These include two weekly injections of the ADA gene product (an enzyme) for life, antibiotics, antifungals, and monthly immunoglobulin infusions full of antibodies to help stave off disease. Alternatively, a bone marrow transplant will also work, but this can only occur if a match is found for the child.
The one child for whom the treatment did not work was older, at 15 years old, while most of the others were significantly younger. This suggests that the treatment may not be as effective in older children.
One serious concern highlighted in this study was an effect of the therapy on certain genes involved in cell growth. Of course, the first question that comes to mind following such an observation is whether or not these effects might lead to cancer, though none of the patients in this specific study presented with tumours or leukemia. Still, such a serious safety issue inevitably contributed to Dr. Kohn and colleagues’ transition away from retroviral vector-based gene delivery systems (like the one used in this trial) and towards lentiviral vectors, which are safer and even more effective. Click here to read about his team’s involvement in clinical trials studying lentiviral gene therapy for ADA-SCID, wherein the immune systems of 48 of 50 children were recovered successfully.
Hybrid nanoparticles for siRNA delivery
Short interfering RNA (siRNA) molecules are genetic materials that have the unique and powerful ability to inhibit the translation of a pathological gene product. Researchers have been looking for efficient, non-toxic delivery systems to bring them into target cells as therapeutic agents since, without one, challenges include their instability, immunogenicity, and general inability to reach the cytosol of a cell on their own. Existing systems, including conjugates and lipid-based nanoparticles, are generally inefficient. Also the lipids, in particular, have been found to be hepatotoxic.
Looking to nature for solutions, the field has tapped extracellular vesicles (EVs) as a potential answer to these issues. EVs are small, naturally-occurring RNA carrier vesicles secreted by many different cell types. They can often be found lugging cargo including RNA, proteins, lipids, or sugars. What advantages are offered by this system? They may be more efficacious in their payload delivery, offer better cell type-specific targeting, lower immunogenicity or toxicity, and may even induce regenerative effects. The caveat: it’s tough to load them with your RNA molecules – much tougher than it is to load synthetic delivery systems.
Evers et al. proposed a biomimetic solution: the EV-liposome, a hybrid nanoparticle with the attractive properties of both natural and artificial systems. There’s quite a lot of chemistry in this paper, but it makes for a really interesting read! Check out their best-of-both worlds system here.
Additional recommendations
Here are some papers/headlines that I didn’t have room for above:
A microfluidic platform enables comprehensive gene expression profiling of mouse retinal stem cells. Coles et al. in Lab on a Chip.
MEndR: An In Vitro Functional Assay to Predict In Vivo Muscle Stem Cell-Mediated Repair. Davoudi et al. in Advanced Functional Materials.
StemBond hydrogels control the mechanical microenvironment for pluripotent stem cells. Labouesse et al. in Nature Communications.
Lithium treatment and human hippocampal neurogenesis. Palmos et al. in Translational Psychiatry.
Human ALS/FTD brain organoid slice cultures display distinct early astrocyte and targetable neuronal pathology. Szebényi et al. in Nature Neuroscience.
Escape of hair follicle stem cells causes stem cell exhaustion during aging. Zhang et al. in Nature Aging.
Introducing dorsoventral patterning in adult regenerating lizard tails with gene-edited embryonic neural stem cells. Lozito et al. in Nature Communications.
Human neural tube morphogenesis in vitro by geometric constraints. Karzbrun et al. in Nature.
Wip1 regulates the immunomodulatory effects of murine mesenchymal stem cells in type 1 diabetes mellitus via targeting IFN-α/BST2. Zhou et al. in Cell Death Discovery.
Stem Cell Transplant Seen as Major Type 1 Diabetes Advance. Miriam Tucker for Medscape.
Inducible cardiomyocyte injury within the atrioventricular conduction system uncovers latent regenerative capacity in mice. Wang et al. in The Journal of Clinical Investigation.
Skeletal muscle regeneration with robotic actuation–mediated clearance of neutrophils. Seo et al. in Science Translational Medicine.
Newly regenerated axons via scaffolds promote sub-lesional reorganization and motor recovery with epidural electrical stimulation. Siddiqui et al. in npj Regenerative Medicine.
New public-private consortium will tackle gene therapies for rare diseases. Kari Oakes for Regulatory Affairs Professionals Society.
Bone marrow CD73+ mesenchymal stem cells display increased stemness in vitro and promote fracture healing in vivo. Kimura et al. in Bone Reports.
Integrated loss- and gain-of-function screens define a core network governing human embryonic stem cell behavior. Naxerova et al. in Genes & Development.
Functional characterization of a bioengineered liver after heterotopic implantation in pigs. Anderson et al. in Communications Biology.
Resolvin-D2 targets myogenic cells and improves muscle regeneration in Duchenne muscular dystrophy. Dort et al. in Nature Communications.
The serine proteases dipeptidyl-peptidase 4 and urokinase are key molecules in human and mouse scar formation. Vorstandlechner et al. in Nature Communications.
Shaping modern human skull through epigenetic, transcriptional and post-transcriptional regulation of the RUNX2 master bone gene. Di Pietro et al. in Scientific Reports.
Human retinal organoids release extracellular vesicles that regulate gene expression in target human retinal progenitor cells. Zhou et al. in Scientific Reports.
Analysis of the early response to spinal cord injury identified a key role for mTORC1 signaling in the activation of neural stem progenitor cells. Peñailillo et al. in npj Regenerative Medicine.
Nerve growth factor (NGF) with hypoxia response elements loaded by adeno-associated virus (AAV) combined with neural stem cells improve the spinal cord injury recovery. Wu et al. in Cell Death Discovery.
Auto-qPCR; a python-based web app for automated and reproducible analysis of qPCR data. Maussion et al. in Scientific Reports.
An inducible p21-Cre mouse model to monitor and manipulate p21-highly-expressing senescent cells in vivo. Wang et al. in Nature Aging.
Systematic review and meta-analysis of preclinical studies testing mesenchymal stromal cells for traumatic brain injury. Pischiutta et al. in npj Regenerative Medicine.
Transcriptomic analysis of loss of Gli1 in neural stem cells responding to demyelination in the mouse brain. Samanta et al. in Scientific Data.
Stay tuned for my next post, coming up in November!
Lyla El-Fayomi
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