Tag: Stem Cells

Research sheds light on post-sepsis immune suppression mechanism

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Severe sepsis from bacterial or viral infections can be life-threatening and even people recovering from severe sepsis may experience long-lasting effects on the immune system, making them more susceptible to recurrent infections. The causes for this sepsis-induced immune suppression are not well understood and lack an effective treatment. To better understand the cause, Katherine MacNamara and colleagues from Albany Medical College, USA, analyzed the blood stem cells of mice with prior sepsis and their results were recently published in the journal Stem Cell Reports.

During acute infection, blood stem cells in the bone marrow are activated by signaling molecules called inflammatory cytokines, which make them divide and migrate to the blood stream to generate large quantities of immune cells outside the bone marrow. Once infection is eliminated, cytokine levels return to baseline and blood stem cell activation and immune cell production stops.

To understand how this process gets dysregulated after severe sepsis resolves, the researchers analyzed the blood stem cells of mice and found them to be fully recovered and functional in the bone marrow of mice 20 days after sepsis. However, upon a second round of inflammatory stimulation, using the stem cell mobilizing agent G-CSF, the blood stem cells of sepsis survivors did not undergo a new round of activation and mobilization as did those in mice without prior sepsis.

Consequently, immune cells were not efficiently produced in those mice with prior sepsis. These observations could explain why following sepsis, patients are unable to efficiently combat new infections and why giving inflammatory cytokines and G-CSF specifically to sepsis patients had no effect against secondary infections in previous clinical trials. This knowledge may help to identify new treatments for patients with post-sepsis immune suppression.

Source:

International Society for Stem Cell Research

Journal reference:

Biswas, N., et al. (2024) Survivors of polymicrobial sepsis are refractory to G-CSF-induced emergency myelopoiesis and hematopoietic stem and progenitor cell mobilization. Stem Cell Reports. doi.org/10.1016/j.stemcr.2024.03.007.

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April 13, 2024
Research offers insights into facial development at the cellular level

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Mother Nature is an artist, but her craft of creating animal faces requires more than a paintbrush and palette. Such highly complex shapes originate from their respective transient neural crest cells.

These embryonic pluripotent cells within the facial primordium-;the early development form-;may be necessary for forming proper facial structures. However, analyzing the molecular mechanisms in such early stages of development poses many technical challenges.

Now, a group of Kyoto University researchers have produced neural crest cell-rich aggregates from human pluripotent stem cells and developed a method to differentiate them in cell populations with a branchial arch-like gene expression pattern.

After the cell populations differentiate into precursors of maxillary and mandibular cells in response to external signaling factors, these populations spontaneously form patterns of the facial primordium.”

Yusuke Seto of KyotoU’s Institute for Medical and Biological Research

This cartilage-like structure, reminiscent of Meckel‘s cartilage, is formed locally within the aggregates.

“We aim to establish a model for studying early facial development by using the properties of human pluripotent stem cells to generate in vitro tissue resembling the bronchial arch of the primordial face,” adds Ryoma Ogihara, also of the Institute.

Researchers are examining the various developmental processes that cause interspecific and individual differences in facial structure to explain conditions such as craniofacial disorders.

“Using our in vitro model could help us better understand and control signal integration during the fate determination of the branchial arch and cartilage formation in the face and elsewhere. We hope our technology can contribute to the development of cellular materials for new regenerative medicine,” adds Mototsugu Eiraku, also of the Institute.

Source:

Journal reference:

Seto, Y., et al. (2024). In vitro induction of patterned branchial arch-like aggregate from human pluripotent stem cells. Nature Communications. doi.org/10.1038/s41467-024-45285-0.

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April 12, 2024
Human neuron model identifies potential therapeutic targets for Alzheimer’s disease

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Weill Cornell Medicine scientists have developed an innovative human neuron model that robustly simulates the spread of tau protein aggregates in the brain-;a process that drives cognitive decline in Alzheimer’s disease and frontotemporal dementia. This new model has led to the identification of novel therapeutic targets that could potentially block tau spread.

The preclinical study, published April 5 in Cell, is a significant advancement in Alzheimer’s disease research.

Currently no therapies can stop the spread of tau aggregates in the brains of patients with Alzheimer’s disease. Our human neuron model of tau spread overcomes the limitations of previous models and has unveiled potential targets for drug development that were previously unknown.”

Dr. Li Gan, lead study author, director of the Helen and Robert Appel Alzheimer’s Disease Research Institute and the Burton P. and Judith B. Resnick Distinguished Professor in Neurodegenerative Diseases in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine

Human pluripotent stem cells can develop into any cell of the body and can be coaxed to become neurons to model brain diseases in a lab dish. However, it had been nearly impossible to model tau propagation in these young neurons, as tau propagation requires decades in aging brains.

Dr. Gan’s team used CRISPR technology to modify the genomes of human stem cells, prompting them to express forms of tau associated with diseased aging brains. “This model has been a game-changer, simulating tau spread in neurons within weeks-;a process that would typically take decades in the human brain,” Dr. Gan said.

In their quest to halt tau propagation, Dr. Gan’s team employed CRISPRi screening to disable one thousand genes to ascertain their roles in tau spread. They discovered 500 genes that have a significant impact on tau abundance.

“CRISPRi technology allowed us to use unbiased approaches to look for drug targets, not confined to what was previously reported by other scientists,” said one of the lead study authors Celeste Parra Bravo, a neuroscience doctoral candidate in the Weill Cornell Graduate School of Medical Sciences working in the Gan lab.

One discovery includes the UFMylation cascade, a cellular process involving the attachment of a small protein named UFM1 to other proteins. This process’s connection to tau spread was previously unknown. Post-mortem studies of brains from patients with Alzheimer’s disease found that UFMylation is altered, and the team also found in preclinical models that inhibition of the enzyme required for UFMylation blocks tau propagation in neurons.

“We are particularly encouraged by the confirmation that inhibiting UFMylation blocked tau spread in both human neurons and mouse models,” said paper co-author Dr. Shiaoching Gong, associate professor of research in neuroscience in the Appel Institute at Weill Cornell Medicine.

Many Alzheimer’s disease treatments initially show promise in mouse models but do not succeed in clinical trials, Dr. Gan said. With the new human cell model, she is optimistic about the path ahead. “Our discoveries in human neurons open the door to developing new treatments that could truly make a difference for those suffering from this devastating disease.”

Source:

Journal reference:

Bravo, C. P., et al. (2024) Human iPSC 4R tauopathy model uncovers modifiers of tau propagation. Cell. doi.org/10.1016/j.cell.2024.03.015.

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April 5, 2024
Gene therapy and glycoside drugs offer new hope for polycystic kidney disease treatment

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Researchers have shown that dangerous cysts, which form over time in polycystic kidney disease (PKD), can be prevented by a single normal copy of a defective gene. This means the potential exists that scientists could one day tailor a gene therapy to treat the disease. They also discovered that a type of drug, known as a glycoside, can sidestep the effects of the defective gene in PKD. The discoveries could set the stage for new therapeutic approaches to treating PKD, which affects millions worldwide. The study, partially funded by the National Institutes of Health (NIH), is published in Cell Stem Cell.

Scientists used gene editing and 3-D human cell models known as organoids to study the genetics of PKD, which is a life-threatening, inherited kidney disorder in which a gene defect causes microscopic tubes in the kidneys to expand like water balloons, forming cysts over decades. The cysts can crowd out healthy tissue, leading to kidney function problems and kidney failure. Most people with PKD are born with one healthy gene copy and one defective gene copy in their cells.

Human PKD has been so difficult to study because cysts take years and decades to form. This new platform finally gives us a model to study the genetics of the disease and hopefully start to provide answers to the millions affected by this disease.”

Benjamin Freedman, Ph.D., senior study author at the University of Washington, Seattle

To better understand the genetic reasons cysts form in PKD, Freedman and his colleagues sought to determine if 3-D human mini-kidney organoids with one normal gene copy and one defective copy would form cysts. They grew organoids, which can mimic features of an organ’s structure and function, from induced pluripotent stem cells, which can become any kind of cell in the body.

To generate organoids containing clinically relevant mutations, the researchers used a gene editing technique called base editing to create mutations in certain locations on the PKD1 and PKD2 genes in human stem cells. They focused on four types of mutations in these genes that are known to cause PKD by disrupting the production of polycystin protein. Disruptions in two types of the protein – polycystin-1 and polycystin-2 – are associated with the most severe forms of PKD.

They then compared cells with two gene copy mutations in organoids to cells with only one gene copy mutation. In some cases, they also used gene editing to correct mutations in one of the two gene copies to see how this affected cyst formation. They found organoids with two defective gene copies always produced cysts and those that carried one good gene copy and one bad copy did not form cysts.

“We didn’t know if having a gene mutation in only one gene copy is enough to cause PKD, or if a second factor, such as another mutation or acute kidney injury was necessary,” Freedman said. “It’s unclear what such a trigger would look like, and until now, we haven’t had a good experimental model for human PKD.”

According to Freedman, the cells with one healthy gene copy make only half the normal amount of polycystin-1 or polycystin-2, but that was sufficient to prevent cysts from developing. He added that the results suggest the need for a second trigger and that preventing that second hit might be able to prevent the disease.

The organoid models also provided the first opportunity to study the effectiveness of a class of drugs known as eukaryotic ribosomal selective glycoside on PKD cyst formation.

“These compounds will only work on single base pair mutations, which are commonly seen in PKD patients,” explained Freedman. “They wouldn’t be expected to work on any mouse models and didn’t work in our previous organoid models of PKD. We needed to create that type of mutation in an experimental model to test the drugs.”

Freedman’s team found that the drugs could restore the ability of genes to make polycystin, increasing the levels of polycystin-1 to 50% and preventing cysts from forming. Even after cysts had formed, adding the drugs slowed their growth.

Freedman suggested that a next step would be to test existing glycoside drugs in patients. Researchers also could explore the use of gene therapy as a treatment for PKD.

The research was supported by NIH’s Nation Center for Advancing Translational Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, and National Institute of General Medical Sciences through awards R01DK117914, UH3TR002158, UH3TR003288, U01DK127553, U01AI176460, U2CTR004867, UC2DK126006, P30DK089507, R21DK128638, and R35GM142902; an Eloxx Pharmaceuticals Award; the Lara Nowak-Macklin Research Fund; and a Washington Research Foundation fellowship.

Source:

NIH/National Center for Advancing Translational Sciences (NCATS)

Journal reference:

Vishy, C. E., et al. (2024) Genetics of cystogenesis in base-edited human organoids reveal therapeutic strategies for polycystic kidney disease. Cell Stem Cell. doi.org/10.1016/j.stem.2024.03.005.

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April 5, 2024
Stem cell therapy safe and potentially beneficial for spinal cord injury patients

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A Mayo Clinic study shows stem cells derived from patients’ own fat are safe and may improve sensation and movement after traumatic spinal cord injuries. The findings from the phase 1 clinical trial appear in Nature Communications. The results of this early research offer insights on the potential of cell therapy for people living with spinal cord injuries and paralysis for whom options to improve function are extremely limited.

In the study of 10 adults, the research team noted seven participants demonstrated improvements based on the American Spinal Injury Association (ASIA) Impairment Scale. Improvements included increased sensation when tested with pinprick and light touch, increased strength in muscle motor groups, and recovery of voluntary anal contraction, which aids in bowel function. The scale has five levels, ranging from complete loss of function to normal function. The seven participants who improved each moved up at least one level on the ASIA scale. Three patients in the study had no response, meaning they did not improve but did not get worse.

This study documents the safety and potential benefit of stem cells and regenerative medicine. Spinal cord injury is a complex condition. Future research may show whether stem cells in combination with other therapies could be part of a new paradigm of treatment to improve outcomes for patients.”

Mohamad Bydon, M.D., a Mayo Clinic neurosurgeon and first author of the study

No serious adverse events were reported after stem cell treatment. The most commonly reported side effects were headache and musculoskeletal pain that resolved with over-the-counter treatment.

In addition to evaluating safety, this phase 1 clinical trial had a secondary outcome of assessing changes in motor and sensory function. The authors note that motor and sensory results are to be interpreted with caution given limits of phase 1 trials. Additional research is underway among a larger group of participants to further assess risks and benefits.

The full data on the 10 patients follows a 2019 case report that highlighted the experience of the first study participant who demonstrated significant improvement in motor and sensory function.

Stem cells’ mechanism of action not fully understood

In the multidisciplinary clinical trial, participants had spinal cord injuries from motor vehicle accidents, falls and other causes. Six had neck injuries; four had back injuries. Participants ranged in age from 18 to 65.

Participants’ stem cells were collected by taking a small amount of fat from a 1- to 2-inch incision in the abdomen or thigh. Over four weeks, the cells were expanded in the laboratory to 100 million cells and then injected into the patients’ lumbar spine in the lower back. Over two years, each study participant was evaluated at Mayo Clinic 10 times.

Although it is understood that stem cells move toward areas of inflammation -; in this case the location of the spinal cord injury -; the cells’ mechanism of interacting with the spinal cord is not fully understood, Dr. Bydon says. As part of the study, researchers analyzed changes in participants’ MRIs and cerebrospinal fluid as well as in responses to pain, pressure and other sensation. The investigators are looking for clues to identify injury processes at a cellular level and avenues for potential regeneration and healing.

The spinal cord has limited ability to repair its cells or make new ones. Patients typically experience most of their recovery in the first six to 12 months after injuries occur. Improvement generally stops 12 to 24 months after injury. One unexpected outcome of the trial was that two patients with cervical spine injuries of the neck received stem cells 22 months after their injuries and improved one level on the ASIA scale after treatment.

Two of three patients with complete injuries of the thoracic spine -; meaning they had no feeling or movement below their injury between the base of the neck and mid-back -; moved up two ASIA levels after treatment. Each regained some sensation and some control of movement below the level of injury. Based on researchers’ understanding of traumatic thoracic spinal cord injury, only 5% of people with a complete injury would be expected to regain any feeling or movement.

“In spinal cord injury, even a mild improvement can make a significant difference in that patient’s quality of life,” Dr. Bydon says.

Research continues into stem cells for spinal cord injuries

Stem cells are used mainly in research in the U.S., and fat-derived stem cell treatment for spinal cord injury is considered experimental by the Food and Drug Administration.

Between 250,000 and 500,000 people worldwide suffer a spinal cord injury each year, according to the World Health Organization.

An important next step is assessing the effectiveness of stem cell therapies and subsets of patients who would most benefit, Dr. Bydon says. Research is continuing with a larger, controlled trial that randomly assigns patients to receive either the stem cell treatment or a placebo without stem cells.

“For years, treatment of spinal cord injury has been limited to supportive care, more specifically stabilization surgery and physical therapy,” Dr. Bydon says. “Many historical textbooks state that this condition does not improve. In recent years, we have seen findings from the medical and scientific community that challenge prior assumptions. This research is a step forward toward the ultimate goal of improving treatments for patients.”

Dr. Bydon is the Charles B. and Ann L. Johnson Professor of Neurosurgery. This research was made possible with support from Leonard A. Lauder, C and A Johnson Family Foundation, The Park Foundation, Sanger Family Foundation, Eileen R.B. and Steve D. Scheel, Schultz Family Foundation, and other generous Mayo Clinic benefactors. The research is funded in part by a Mayo Clinic Transform the Practice grant.

Source:

Journal reference:

Bydon, M., et al. (2024). Intrathecal delivery of adipose-derived mesenchymal stem cells in traumatic spinal cord injury: Phase I trial. Nature Communications. doi.org/10.1038/s41467-024-46259-y.

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April 1, 2024
New treatment rejuvenates elderly defenses
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In a recent study published in Nature, researchers developed a treatment to restore the immunological system to a younger condition, with fewer myeloid-biased output-hematopoietic stem cells (my-HSCs), more HSCs, and a balanced generation of myeloid and lymphoid lineage cells (bal-HSCs).

Study: Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity. Image Credit: Lightspring / Shutterstock.com

The effects of aging on the immune system

The aging immune system is associated with reduced lymphopoiesis, increased inflammation, and myeloid diseases due to alterations in self-renewing HSCs. During childhood, bal-HSCs predominate, thereby facilitating lymphopoiesis and adaptive immune responses.

Age increases my-HSCs, which reduces lymphopoiesis and enhances myelopoiesis. Myeloid-HSC origin and possible interconversions are unclear; however, removing my-HSCs in aged mice may reverse the aging phenotype.

About the study

The researchers investigated whether antibody-regulated reduction of my-HSCs may cure age-related immunological reductions by restricting myeloid cell-induced inflammation and restoring lymphopoiesis. To this end, the impact of reduced my-HSCs on the hematopoietic system, immunological phenotypes, and functional responses to incident infections was assessed.

Several cell-surface antigen molecules were developed and validated to identify potential targets for therapeutic my-HSC reduction. The levels of my-HSCs and balanced-HSCs were determined using antibodies and flow cytometry.

Several my-HSC antigens, including neogenin 1 (NEO1), cluster of differentiation 62p (CD62p), and CD150, were subsequently targeted to determine their role in reducing my-HSC levels. Separate antibody-conditioning treatments were then developed for my-HSC depletion for each target, with a focus on cell clearance regulators such as anti-phagocytic signals, isotype, and antibody density.

To establish the role of CD150 targeting, the ability of CD150-targeted antibodies to reduce my-HSCs in vivo was assessed. To target CD62p or NEO1, goat anti-mouse NEO1 antisera was mixed with anti-CD47 and anti-KIT antibodies.

Gene expression analysis of pure total HSCs extracted from 11-month-old mice was performed to confirm alterations in HSC composition following my-HSC elimination. Transplant tests using pure HSCs were also performed to compare the myeloid and lymphoid lineage potential in recipient mice.
After antibody conditioning, myeloid and common lymphocyte progenitors (CLPs) were measured in murine bone marrow. These analyses were performed after one week to assess acute effects, as well as after eight and sixteen weeks to determine long-term effects. The impact of this treatment on non-self-renewing progenitors was also evaluated after eight weeks.

T-cell subsets were analyzed using canonical markers or cluster-based analysis. The effects of my-HSC depletion in aged animals on pro-inflammatory mediators and functional immunity to infection were also examined by analyzing mouse immune responses to a live-attenuated virus and subsequent challenge with a pathogenic viral infection using the mouse Friend retrovirus (FV) model.

Study findings

Antibody-mediated reduction of my-HSCs in elderly mice restored young immune system characteristics, such as increased CLPs, naïve T-cells, and B-cells, while lowering immunological decline indicators associated with aging. Depletion of my-HSCs in old mice increased primary and secondary adaptive immune responses to viral infection.

Twelve potential genes that encode cell-surface proteins significantly expressed in aged HSCs and my-HSCs were identified. Moreover, CD150, CD4, CD6, CD62p20, and NEO1 were identified as markers for my-HSCs.

Antibodies to CD41 and NEO1 enhanced the frequency of my-HSC staining, thus indicating myeloid bias. CD62p targeting resulted in the highest my-HSC enrichment.

The most abundant protein molecules on my-HSCs were NEO1, CD41, and CD62p. Flow cytometry analysis did not identify any surface protein strongly expressed by the subgroups, except CD41, which was highly expressed by megakaryocyte progenitor cells.

Anti-CD150 antibodies significantly reduced my-HSCs in mice, thereby increasing naïve T-cell and mature B-cell levels. In aged mice, CD4+ T lymphocytes with an exhausted phenotype (PD1+ CD62L-) grew more than those with a non-exhausted phenotype (PD1- CD62L+).

Antibody training reduced CD4+ PD1+ CD62L- cells as compared to CD4+ PD1- CD62L+. Aged mice also acquired age-associated B-cells associated with impaired humoral immunity.

Antibody training reduced the levels of pro-inflammatory proteins including interleukin-1 alpha (IL-1α), and C‐X‐C motif chemokine ligand 5 (CXCL5), which were higher in elderly animals. Aged animals with my-HSC depletion exhibited higher virus-specific CD8+ T-cell responses in the spleen following vaccination, thus indicating a better initial response to live-attenuated viral infection.

Conclusions

Rising my-HSC levels during aging may result in inadequate adaptive immunological and inflammatory responses. Thus, depleting my-HSCs may improve immune responses by enhancing the synthesis of new T- and B-cells while decreasing the production of inflammatory myeloid cells. In the current study, my-HSC depletion in older animals allowed bal-HSCs to recover youthful immunological characteristics such as enhanced lymphocyte progenitors and naïve cells and decreased lymphocyte dysfunction or exhaustion indicators and inflammatory mediators.

Further research could refine conditioning techniques and examine the impact on differentiated cells, such as regulatory T-cells.
Journal reference:

Ross, J. B., Myers, L. M., Noh, J. J., et al. (2024). Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity. Nature. doi:10.1038/s41586-024-07238-x
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April 1, 2024
Household chemicals endanger brain’s myelin-forming cells

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In a recent study published in the journal Nature Neuroscience, researchers in the United States pinpointed and evaluated environmental chemicals that hinder oligodendrocyte development through varied mechanisms, assessing their neurodevelopmental impacts.

Study: Pervasive environmental chemicals impair oligodendrocyte development. Image Credit: Lightspring / Shutterstock

Background

Human exposure to environmental chemicals, especially during the critical developmental stages of children’s central nervous systems, raises significant health concerns. Substances like methylmercury, lead, and polychlorinated biphenyls are linked to disrupting brain development, potentially contributing to the increasing prevalence of neurodevelopmental disorders such as autism and Attention-Deficit/Hyperactivity Disorder (ADHD). These trends suggest that environmental factors play a critical role beyond genetics. Oligodendrocytes, vital for brain functionality through myelination and neuronal support, are particularly susceptible to these chemicals from fetal development into adolescence. Despite their significance, limited research has focused on the impact of environmental toxins on oligodendrocytes. This gap highlights the need for further investigation into how these chemicals affect oligodendrocyte development and identifying ways to counteract their detrimental effects on neurodevelopment.

About the study

The present study adhered to ethical standards set by the International Society for Stem Cell Research and the National Institutes of Health, receiving approval from the Case Western Reserve University Institutional Animal Care and Use Committee. Mouse oligodendrocyte precursor cells (OPCs) were cultured from induced pluripotent stem cells (iPSCs), following established protocols that involved removing iPSCs from a feeder layer, dissociating them, and then cultivating them in a medium conducive to OPC expansion and maturation. The culture medium was switched on the tenth day to promote OPC development, utilizing a specific combination of supplements to enrich OPC populations. Additionally, primary mouse OPCs and astrocytes were derived from dissected mouse brain tissue, with the cells undergoing culture in specially prepared media to encourage the growth of OPCs and astrocytes, respectively.

Human cortical organoids were generated from embryonic stem cells and iPSCs, following rigorous stem cell research guidelines. These organoids were cultured in a medium optimized for OPC expansion and differentiation, incorporating various growth factors and supplements. Chemical screening on OPCs utilized the United States Environmental Protection Agency (US EPA) Toxicity Forecaster chemical library to identify compounds that disrupt OPC development.

Various methods, including immunocytochemistry, high-content imaging, and cell viability assays, were employed to assess the impact of chemicals on OPCs. Additionally, the study explored the effects of specific quaternary compounds on cell viability, employing a range of experimental setups across different cell types to understand the compounds’ toxicity profiles.

Study results

The present study developed a high-throughput screening method to assess the impact of environmental chemicals on the development of mouse pluripotent stem cells (mPSCs)- derived OPCs into oligodendrocytes. Among the 1,823 chemicals screened, a selection was found to either be cytotoxic to developing oligodendrocytes or impede their generation without inducing cytotoxicity. The screening revealed that a majority of the chemicals had no significant effect on oligodendrocyte development or viability, yet 292 were identified as cytotoxic and 47 as inhibitors of oligodendrocyte generation.

Further investigation using the MTS assay, which measures metabolic activity as an indicator of cell viability, validated the cytotoxic effects of certain chemicals. Comparison of cytotoxicity profiles across different cell types, including mouse astrocytes and data from the US EPA, identified quaternary compounds as selectively cytotoxic to oligodendrocytes. These compounds, characterized by a central nitrogen with four alkyl groups, demonstrated a specific toxicological sensitivity in developing oligodendrocytes. The study also explored the activation of the integrated stress response (ISR) as a potential mechanism for the cytotoxicity induced by quaternary compounds.

Quaternary compounds were also tested for their ability to cross the blood-brain barrier and were found to be present in brain tissue at nanomolar concentrations following administration to mice. Furthermore, the study extended to human pluripotent stem cell-derived regionalized neural organoid models, confirming that quaternary compounds could disrupt human oligodendrocyte development, reducing the density of SOX10+ OPCs and oligodendrocytes.

Additionally, the screening identified organophosphate flame retardants as inhibitors of oligodendrocyte development. These compounds were shown to arrest the progression of early to intermediate and mature oligodendrocytes. The study’s findings were extended to in vivo and in vitro models of human brain development, demonstrating that exposure to organophosphate flame retardants, particularly Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), significantly reduced the number of SOX10+CC1+ oligodendrocytes in both mouse and human models.

Lastly, the study utilized data from the National Health and Nutrition Examination Survey (NHANES) to investigate associations between exposure to organophosphate flame retardants and neurodevelopmental outcomes in children. High levels of urinary Bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), a metabolite indicative of TDCIPP exposure, were associated with an increased likelihood of special education needs and gross motor dysfunction, suggesting a strong link between organophosphate flame retardant exposure and adverse neurodevelopmental outcomes.

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March 27, 2024
Powerful microscopy reveals blood-cell production in bone marrow
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- NEWS AND VIEWS
- 20 March 2024
A method for imaging the production of blood cells in the bones of mice has revealed the organization of cell lineages, both in a steady state and in response to stressors, such as bleeding and infection.
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March 20, 2024
Study unlocks the mystery of neonatal neutropenia in newborns

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Compared to adults, newborns are highly susceptible to infections and these infections can cause serious health complications and even death.

One factor known to affect a newborn’s response to infection is a condition called neonatal neutropenia, in which the infant fails to make enough neutrophils, the immune system’s first responders. What underlies this immune deficiency, which greatly increases a newborn’s susceptibility to infection, is largely unknown, leaving clinicians with little understanding of how to prevent or treat it.

A new study of mice by Columbia University researchers now suggests that many cases of neonatal neutropenia may originate from suppression of the fetus’s blood-forming stem cells, a natural maternal mechanism that protects the placenta from inflammation but may leave newborns vulnerable to infection if not turned off after birth.

We still have much to learn about neonatal neutropenia, but this is an encouraging step forward in developing new treatments. Our findings tell us that it may be more productive to counteract maternal factors that suppress fetal and neonatal hematopoietic stem cells, instead of trying to directly boost the output of these cells.”

Emmanuelle Passegué, PhD, Alumni Professor of Genetics & Development at the Vagelos College of Physicians and Surgeons and director of the Columbia Stem Cell Initiative at Columbia University

The clinical challenge

Infants with neonatal neutropenia can develop early-onset sepsis, a life-threatening infection, in the first 72 hours of life.

“Early sepsis is a big problem in full-term infants, but it’s even more dangerous for preterm infants and mortality for these infants is very high,” says first author Amélie Collins, MD, PhD, assistant professor of pediatrics and a neonatologist who treats these hospitalized infants.

Doctors use broad-spectrum antibiotics to treat infants with early-onset sepsis, but antibiotics aren’t always enough and often produce other complications. “A treatment that boosts these infants’ immune system could have a big impact,” Collins says.

The prevailing theory of neonatal neutropenia is that fetuses and neonates with the condition lack the regenerative capacity to produce large numbers of neutrophils to fight infection.

“But what that actually means from a mechanistic standpoint has been unknown,” Collins says. “Perinatal hematopoiesis has been an understudied area of biology.”

Experiments and results

To understand how neutropenia develops in infants, Collins and Passegué used mouse models to investigate how fetal and neonatal hematopoietic stem cells respond to infection.

Adults with infections usually rely on emergency myelopoeisis, a rapid-response mechanism of hematopoietic stem cells that generates large numbers of immune cells, including neutrophils.

Collins and Passegué found that although emergency myelopoeisis becomes functional early in fetal development-;the fetus’s hematopoietic stem cells are capable of making neutrophils-;the fetus does not turn it on.

That suggested an external factor suppresses fetal myelopoeisis, so the researchers then searched for and found a maternal factor-;interleukin 10 or IL-10-;that prevents emergency myelopoiesis from being activated during fetal development. Collins and Passegué found that absence of IL-10 can restore emergency myelopoiesis in the fetus and boost neonatal neutrophil production in a manner that is likely to have important clinical benefits.

“This is the key translational advance of our study,” says Collins. “Now that we know fetal and neonatal stem cells can produce neutrophils and we’ve identified IL-10 as one of the factors that suppresses emergency myelopoiesis, we should be able to understand the mechanism and find places where we can intervene.”

Potential impact and future directions

The discovery was also made possible with a second mouse model developed by the researchers that allowed them to track what happens in mouse pups after they’re born (because removing IL-10 comes at the cost of fetal demise in infected pregnant mice).

This second model showed that newborn pups can engage emergency myelopoiesis pathways after they are born and will be crucial for future studies.

“We are now able to learn more about how maternal IL-10 suppresses fetal hematopoietic stem cells and what signals remove the restraints after birth to turn these exciting findings into an effective therapy,” says Passegué.

Source:

Columbia University Irving Medical Center

Journal reference:

Collins, A., et al. (2024). Maternal inflammation regulates fetal emergency myelopoiesis. Cell. doi.org/10.1016/j.cell.2024.02.002.

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March 15, 2024
Scientists develop robust iPSC-derived rejuvenated T lymphocytes for cervical cancer treatment

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Cervical cancer is among the most common malignancies affecting women worldwide. In 2020 alone, approximately 600,000 women were diagnosed with this disease, and over 314,000 died from it. In 99% of the cases, cervical cancer cells harbor human papilloma virus (HPV), and thus, HPV vaccines are an effective way to mitigate the risk of developing this disease. Unfortunately, such preventive measures are useless against established cancers, which are generally incurable once they become metastatic or relapsing.

Fortunately, scientists have made substantial progress in developing a promising therapeutic strategy for cervical cancer: rejuvenated cytotoxic T lymphocytes (rejTs). These lymphocytes can be engineered to target HPV-specific antigens that are expressed predominantly in cervical cancer cells, constituting a type of targeted immunotherapy. Ideally, rejTs would be produced from induced pluripotent stem cells (iPSCs) gathered from the patient themselves. However, this process is not clinically feasible in terms of both time and cost.

Against this backdrop, a research team including Chief Professor Miki Ando, graduate student Yoshiki Furukawa, and Assistant Professor Midori Ishii from Juntendo University School of Medicine, Japan, has recently achieved a breakthrough by developing robust iPSC-derived rejTs for cervical cancer treatment. Their work was published online on December 12, 2023, in Cell Reports Medicine.

The team sought to address one of the key roadblocks for allogeneic iPSC-derived rejTs, which refers to rejTs produced from ‘standardized’ iPSCs rather than derived from the patient’s cells. Prof. Ando explains, “In immunocompetent cervical cancer patients, the dominant problem is the rejection of foreign T lymphocytes by the recipient’s CD8+ T lymphocytes or natural killer (NK) cells.” The patient’s immune system tends to attack the therapeutic HPV-specific rejTs before they can neutralize cancer cells.

To overcome this issue, the research team used CRISPR-Cas9 two-step “scarless” gene editing on iPSCs derived from an HPV-specific cytotoxic T lymphocyte clone. The first modification was the deletion of all HLA class I antigens from the cells. The role of these surface protein is to present peptides to CD8+ T lymphocytes, which promptly eliminate any cells displaying foreign or anomalous peptides. After the modification, the cells are essentially able to evade detection by CD8+ T lymphocytes.

The second modification involved introducing the limited expression of two specific HLA antigens, namely HLA-A24 and HLA-E. This enabled the engineered cells to evade attacks from NK cells, which specifically target cells lacking these surface antigens. By selecting HLA-A24, the engineered cells are naturally compatible with a significant portion of South American, Eastern Asian, North American, and European populations.

After implementing these modifications using CRISPR-Cas9, the researchers induced the differentiation of the iPSCs into T lymphocytes and tested their ability to fight cervical cancer cells while evading allogeneic immune responses both in vitro and in vivo. These experiments yielded very promising results, as the generated rejTs did not trigger attacks from either CD8+ T cells or NK cells while simultaneously achieving strong cytotoxicity against tumor cells.

Compared to the control group, mice engrafted with cervical cancer cells and injected with the gene-edited rejTs survived longer and exhibited significantly reduced tumor sizes and proliferation index. To gain further insights into the enhanced therapeutic effects of the rejTs, the researchers conducted single-cell RNA sequencing analyses. These analyses revealed that the population of rejTs was highly enriched with tissue resident memory T cells, which establish residence in the mucosa of the cervix and provide stronger protection. Prof. Ando remarks, “We found that the enhanced cytotoxicity against cervical cancer occurred through TGFβ signaling and increased CD103 expression.“

Taken together, the results of this study showcase a powerful method to make iPSC-derived rejTs a viable option to treat one of the most common forms of cancer. Prof Ando concludes, “The HLA-engineered HPV-rejTs obtained using our method provide a sustainable and promising approach toward successful ‘off-the-shelf’ T cell therapy, which could help in overcoming cervical cancer. We are planning on conducting an investigator-initiated clinical trial in 2024.“

Source:

Juntendo University Research Promotion Center

Journal reference:

Furukawa, Y., et al. (2023). iPSC-derived hypoimmunogenic tissue resident memory T cells mediate robust anti-tumor activity against cervical cancer. Cell Reports Medicine. doi.org/10.1016/j.xcrm.2023.101327.

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March 6, 2024