This revolutionary field still faces many challenges, including the nontrivial task of convincing stem cells to differentiate into desired cell types for treatment. And even if the correct cells or tissues are created and can function successfully in the body, immune rejection presents a formidable barrier to their use. To overcome this obstacle, regenerative medicine treatments in use today require systemic immunosuppression, leaving patients vulnerable to environmental hazards like viruses, bacteria and cancer cells.

In a novel approach to tackle these obstacles, researchers at the Medical University of South Carolina and the University of Florida recently collaborated on a novel, highly specific strategy to treat type 1 diabetes (T1D) using a tagged beta cell transplant in tandem with localized immune protection provided by specialized immune cells also tagged with a complementary but inert targeting molecule.

According to Leonardo Ferreira, Ph.D., a researcher at MUSC Hollings Cancer Center and one of the principal investigators on the study, marrying stem cell engineering and regulatory T cell (Treg) engineering allowed the first step toward a readily available, off-the-shelf solution to treating T1D.

In their recent study published in the journal Cell Reports, the researchers described a unique collaboration that leveraged the beta cell engineering expertise of the lab of Holger Russ, an associate professor of pharmacology and therapeutics at the University of Florida, combined with the delicate surgical expertise and chimeric antigen receptor (CAR) T cell expertise available at Hollings.

For T1D patients, the trouble begins with an immune system self-attack on pancreatic beta cells, the cells that produce the hormone insulin to regulate blood sugar levels. Without a reliable way to self-regulate blood glucose levels, patients are forced to live with a high-maintenance regimen of glucose monitoring and insulin management to maintain health and avoid dangerous complications like neuropathy, amputation and blindness.

For now, some patients with poorly controlled T1D may consider islet cell transplantation using beta cells from a donor. Beta cells are isolated from a donor pancreas, purified and delivered to the patient’s liver, where they can take up residence and begin secreting insulin. However, this option requires patients to undergo immunosuppression for the rest of their lives to keep the body from rejecting the foreign beta cells. It also requires the availability of donor cells, which might require long waits or may not happen at all.

To focus on an alternative solution, the researchers used an engineering strategy with tagged beta cells generated from stem cells. And to induce localized immune protection, the researchers chose to use Tregs, a type of immune cell that monitors and controls the immune response.

“Most of the cells of the immune system are focused on killing invasive elements,” Ferreira said. “But Tregs are the generals of the immune system. They make sure that nothing goes overboard, and they train the immune system on how to respond in the future.”

The researchers used a mouse model to test their strategy. By transplanting beta cells that were engineered from stem cells and included a nonreactive tag — an inactivated version of epidermal growth factor receptor — into the kidney capsules of immunodeficient mice, they showed that the cells were incorporated and began to manufacture functional insulin. In the next phase of testing, the mice were exposed to an aggressive type of immune cell to check on the viability of the transplanted beta cells in the face of a simulated immune response. As expected, all of the beta cells were killed by the immune response, the same thing that happens in people with T1D.

To avoid the killing response in the next phase, the researchers added specialized Tregs along with the immune challenge. These cells were tagged with CAR technology using a receptor that specifically recognized the inert EGFR tag present on the transplanted beta cells. With this added step, the researchers observed the immune protection they hoped for, as they observed the transplanted beta cells remaining safe, sound and functional in their new home.

Ferreira was delighted with the results and energized to take the next steps. “With this approach,” he said, “we made both the lock and the key for creating immune tolerance.”

Now that Ferreira and colleagues have shown the feasibility of their approach to T1D treatment, they plan to continue their research efforts, including building a whole library of locks and keys — differentiated stem cells and tagged protective Tregs — for multiple purposes, such as targeting certain cancers, lupus and other autoimmune diseases.

A few questions remain, such as the specific ligand that should be used for human transplantation and the longevity of Treg-mediated immune protection. The ligand or tag must be inert and have no negative impact on the function of the cells or create any reaction that could cause side effects. And it is still unknown if one Treg treatment will be effective or might need to be repeated at intervals that have yet to be established. Because Tregs can educate immune cells to maintain immune tolerance, it is possible that one treatment will be adequate, but further research is needed to understand the long-term effects.

Answering these questions and confirming the validity of the approach in humans may soon transform T1D from a chronic, high-maintenance disease with many complications to one that can be managed much more easily.

“Establishing such biomarkers could provide a key step in changing how we care for, treat, and offer interventions to people with psychosis,” said Brian Keane, PhD, assistant professor of Psychiatry, Center for Visual Science, and Neuroscience at the University of Rochester Medical Center. Keane recently co-authored an article in Molecular Psychiatry that identifies how MRI scans could reveal brain differences in people with psychosis. “Aside from potentially predicting future psychosis onset, biomarkers could also help stratify patients into clinically meaningful subgroups and suggest new options for treatment or intervention.”

Using data collected by the Human Connectome Early Psychosis Project, researchers looked at MRI scans from 159 participants. These included 105 who developed a psychotic disorder up to five years prior to testing. In the brains of participants with psychosis, researchers found that sensory regions in the cortex were more weakly connected to each other and more strongly connected to the thalamus, the brain’s information relay station. These differences were confined to the somatomotor network, which processes bodily movement and sensations, and a visual network, which generates representations of objects, faces, and complex features. Combining the dysconnectivity patterns across these two networks allowed the researchers to create a “somato-visual” biomarker.

Previous research has suggested that abnormal brain connectivity exists prominently in the sensory networks of people with schizophrenia, but it remained unclear which networks were most responsible or whether dysconnectivity could be explained by other illness factors, such as antipsychotic use, anxiety, or stress.

“What makes this biomarker unique is its large effect size, its robustness to over a dozen common confounds, and its high reliability across multiple scans. A single five-minute scan could potentially improve our ability to predict which at-risk individuals will transition to a psychotic disorder, which in turn could allow for more timely treatments or interventions,” Keane said. “It also gives us a place to keep looking. An important next step will be to determine if the somato-visual biomarker emerges before or as psychosis begins.”

Additional authors include Yonatan Abrham, Boyang Hu, and Brent Johnson of the University of Rochester, Carrisa Cocuzza of Yale University, and Michael Cole of Rutgers University. This work was supported by a K01 grant and a Psychiatry Department pilot grant at the University of Rochester.

The study, published Nov. 25 in Nature Aging, may lead to new longevity treatments that could extend human lifespan. It also establishes a mortality timer that reveals how long a cell has left before it dies.

As people get older, they are more likely to develop health conditions, such as cancer, cardiovascular disease and neurodegenerative diseases.

“Aging is the highest risk factor for these diseases,” said Dr. Jessica Tyler, professor of pathology and laboratory medicine at Weill Cornell Medicine. “Rather than treating each disease separately, a better approach would be to develop a therapeutic or supplement that will delay the onset of diseases by preventing the underlying molecular defects that cause them.” The nucleolus may hold the key.

Small Packages

The nucleus holds the cell’s chromosomes and the nucleolus where the ribosomal DNA (rDNA) is housed. The nucleolus isolates the rDNA which encodes the RNA portions of the ribosomes, the protein-building machinery. The rDNA is one of the most fragile parts of the genome, due to its repetitive nature making it more difficult to maintain and fix if damaged. If damage in the rDNA is not accurately repaired, it can lead to chromosomal rearrangements and cell death.

In organisms from yeast to worms to humans, nucleoli expand during aging. On the flip side, anti-aging strategies like calorie restriction, or eating less, result in smaller nucleoli. “Calorie restriction does so many different things, and no one knows the precise way that it is extending lifespan,” Dr. Tyler said.

Dr. Tyler and postdoctoral fellow Dr. J. Ignacio Gutierrez, the first author of the paper, suspected that keeping nucleoli small could delay aging. To test this idea, they engineered an artificial way to secure rDNA to the membrane surrounding the nucleus of yeast cells so they could control when it was anchored and when it was not. “The advantage of our system is that we could isolate the nucleolus size from all of the other effects of anti-aging strategies,” Dr. Gutierrez said.

The researchers discovered that tethering the nucleolus was enough to keep it compact, and small nucleoli delayed aging to about the same extent as calorie restriction.

Final Moments

Interestingly, nucleoli did not expand at the same rate during the entire lifespan as cells aged. They remained small for most of the yeast’s life, but at a nucleolar size threshold, the nucleoli suddenly began to grow quickly and expand to a much larger size. Cells only survived for an average of about five more cell divisions after hitting this threshold.

“When we saw it wasn’t a linear size increase, we knew something really important was happening,” said Dr. Gutierrez. Passing the threshold appears to serve as a mortality timer, ticking down the final moments of a cell’s life.

During aging, DNA accumulates damage, some of which can be devastating to the cell. In tests, the team found that large nucleoli had less stable rDNA than smaller ones. Also, when the structure is large, proteins and other factors that are usually excluded from the nucleolus are no longer kept out. It’s as if the nucleolus becomes leaky, letting in molecules that can wreak havoc on the fragile rDNA.

“The whole point of condensates is to separate biological reactions to help them work efficiently, but now when you have other proteins coming into the nucleolus, it leads to genome instability, which triggers the end of the lifespan,” Dr. Tyler said. These proteins can cause catastrophic problems, such as chromosomal rearrangements, to build up.

Next, the researchers plan to study nucleolar effects on aging in human stem cells. Stem cells are special because they have the potential to replace other cell types as they die. But eventually, the stem cells stop dividing, so the researchers hope to use the knowledge gained from this project to make them last longer.

“I was excited that we could connect the structure of the nucleolus with the repair process in a way that could be conserved from yeast to humans,” said Dr. Gutierrez.

In a new Northwestern Medicine study, scientists sought to better understand how humans evolved to become so skilled at thinking about what’s happening in other peoples’ minds. The findings could have implications for one day treating psychiatric conditions such as anxiety and depression.

“We spend a lot of time wondering, ‘What is that person feeling, thinking? Did I say something to upset them?'” said senior author Rodrigo Braga. “The parts of the brain that allow us to do this are in regions of the human brain that have expanded recently in our evolution, and that implies that it’s a recently developed process. In essence, you’re putting yourself in someone else’s mind and making inferences about what that person is thinking when you cannot really know.”

The study found the more recently evolved and advanced parts of the human brain that support social interactions — called the social cognitive network — are connected to and in constant communication with an ancient part of the brain called the amygdala.

Often referred to as our “lizard brain,” the amygdala typically is associated with detecting threats and processing fear. A classic example of the amygdala in action is someone’s physiological and emotional response to seeing a snake: startled body, racing heart, sweaty palms. But the amygdala also does other things, Braga said.

“For instance, the amygdala is responsible for social behaviors like parenting, mating, aggression and the navigation of social-dominance hierarchies,” said Braga, an assistant professor of neurology at Northwestern University Feinberg School of Medicine. “Previous studies have found co-activation of the amygdala and social cognitive network, but our study is novel because it shows the communication is always happening.”

The study was published Nov. 22 in the journal Science Advances.

High-resolution brain scans were key

Within the amygdala, there’s a specific part called the medial nucleus that is very important for social behaviors. This study was the first to show the amygdala’s medial nucleus is connected to newly evolved social cognitive network regions, which are involved in thinking about other people. This link to the amygdala helps shape the function of the social cognitive network by giving it access to the amygdala’s role in processing emotionally important content.

This was only possible because of functional magnetic resonance imaging (fMRI), a noninvasive brain-imaging technique that measures brain activity by detecting changes in blood oxygen levels. A collaborator at the University of Minnesota and co-author on the study, Kendrick Kay, provided Braga and co-corresponding author Donnisa Edmonds with fMRI data from six study participants’ brains, as part of the Natural Scenes Dataset (NSD). These high-resolution scans enabled the scientists to see details of the social cognitive network that had never been detected on lower-resolution brain scans. What’s more, they were able to replicate the findings up to two times in each individual.

“One of the most exciting things is we were able to identify network regions we weren’t able to see before,” said Edmonds, a neuroscience Ph.D. candidate in Braga’s lab at Northwestern. “That’s something that had been underappreciated before our study, and we were able to get at that because we had such high-resolution data.”

Potential treatment of anxiety, depression

Both anxiety and depression involve amygdala hyperactivity, which can contribute to excessive emotional responses and impaired emotional regulation, Edmonds said. Currently, someone with either condition could receive deep brain stimulation for treatment, but since the amygdala is located deep within the brain, directly behind the eyes, it means having an invasive, surgical procedure. Now, with this study’s findings, a much less-invasive procedure, transcranial magnetic stimulation (TMS), might be able to use knowledge about this brain connection to improve treatment, the authors said.

“Through this knowledge that the amygdala is connected to other brain regions — potentially some that are closer to the skull, which is an easier region to target — that means people who do TMS could target the amygdala instead by targeting these other regions,” Edmonds said.

The study is titled, “The human social cognitive network contains multiple regions within the amygdala.” Other Northwestern co-authors include Christina Zelano, Joseph J. Salvo, Nathan Anderson, Maya Lakshman and Qiaohan Yang.

The study highlights significant racial and socioeconomic disparities, finding that non-Hispanic Black mothers faced more than double the rate of severe complications compared to non-Hispanic white mothers, and that living in high-poverty neighborhoods elevated maternal health risks across all racial groups.

“Despite significant recent statewide quality-improvement efforts, these birth outcomes are worsening for all ages, reflecting the worsening pre-pregnancy health of the reproductive-age population in Illinois,” said corresponding author Dr. Mugdha Mokashi, aresident physician in obstetrics and gynecology at the McGaw Medical Center at Northwestern.

The findings reflect national trends demonstrating the increasing prevalence of conditions such as obesity, hypertensive disorders of pregnancy and gestational diabetes among pregnant people of all ages, she added. The study provides the most updated data on maternal morbidity and delivery complications within the state of Illinois.

The findings were published Nov. 21 in the journal Obstetrics & Gynecology Open.

“Our findings underscore the role of social determinants of health — such as race and income — in driving disparities in maternal health, suggesting that efforts to reduce maternal morbidity need to address both racial inequalities and economic hardship,” said study co-author Dr. Lynn Yee, associate professor of obstetrics and pulmonology at Northwestern University Feinberg School of Medicine and a Northwestern Medicine maternal fetal medicine physician.

Breaking down of the findings:

In the study cohort of 988,480 births at 127 Illinois hospitals between January 2016 to June 2023, the overall rate of severe maternal morbidity rose from 1.4% in 2016 to 2% in 2023. Vaginal birth complications increased 22.4%, and cesarean birth complications increased 48.9%.

Hypertensive disorders of pregnancy and anemia — both of which increased over the study period — were significant risk factors for severe maternal morbidity and birth complications. The largest increase by far was in annual rates of obesity from 2016 to the first six months of 2023 (7.8% to 22.3%). Additionally, there were increases in gestational diabetes (4.2% to 5.5%), depression (2.5% to 6.6%), anxiety (3.1% to 10.4%) and other chronic comorbidities (4.7% to 7.4%). Non-Hispanic Black patients had more than double the severe maternal morbidity rate (2.6%) compared to non-Hispanic white patients (1.1%).

Health counseling before pregnancy is important

Maternal health affects almost everyone, and those thinking about pregnancy should be sure to check in with their health care provider to screen for any chronic conditions they may have before getting pregnant, the study authors said.

“Pre-conception counseling is such an important way to make sure that all of your health conditions are optimized prior to pregnancy,” Mokashi said. “There are many important policy and public health initiatives in Illinois that people may be interested in learning more about.”

‘It’s not just because the people getting pregnant are older’

While not the original aim of the study, the scientists did additional analysis that found the increased prevalence of maternal health issues and birth complications is not simply because the people getting pregnant are older. The findings reflected an increase in hospital coding for hypertensive disorders of pregnancy, gestational diabetes, anemia, depression, serious mental illness and other chronic conditions, especially obesity, even among those giving birth who are younger than 30.

“In brief, even young pregnant patients have more medical conditions and complications in pregnancy,” Mokashi said.

What can be done?

Policies for poverty alleviation — such as the proposed refundable child tax credit in Illinois, House Bill 4917, if passed — have demonstrated improvement in maternal health, the study authors said.

Perinatal quality initiatives in California have reduced postpartum hemorrhage-related morbidity. Similarly, the Illinois Perinatal Quality Collaborative is working to reduce cesarean births and address racial disparities through Promoting Vaginal Birth and Birth Equity initiatives.

Increasing access to doula support and patient navigator programs could also be useful supports, Mokashi said. In 2024, the Illinois Department of Healthcare and Family Services adjusted reimbursement for doula services. At Northwestern, research on patient-navigator programs have shown promise in reducing care disparities for low-income minoritized patients postpartum. And at the federal level, passage of the 13 bills comprising the Black Maternal Health Momnibus Act re-introduced in 2023 would provide critical funding support to increase data collection and quality initiatives for prevention of maternal morbidity.

It’s a core function, but little studied in the setting of cancer immunology, especially when compared to other organelles like the mitochondria or endoplasmic reticulum.

“So we were interested in looking a little bit more at the Golgi apparatus. It’s obviously an important organelle. How is it being changed or what is its role in T-cells in terms of fighting cancer?” said Nathaniel Oberholtzer, an M.D./Ph.D. student who worked in the lab of Shikhar Mehrotra, Ph.D., co-leader of the Cancer Biology & Immunology Research Program at MUSC Hollings Cancer Center and scientific director of the Center for Cellular Therapy in the MUSC College of Medicine.

As it turns out, the healthy function of the Golgi apparatus has a lot to do with how well T-cells function in killing cancer cells. Understanding how a signaling axis mitigates Golgi stress, enabling it to perform properly, points to a possible new therapeutic target for researchers to pursue to strengthen T-cells. Not only that, but Oberholtzer’s research shows how the Golgi could be used as a biomarker to select the strongest T-cells for immunotherapy.

Oberholtzer, as first author, and Mehrotra, as senior author, along with a team of Hollings scientists published the research this month in Science Advances.

T-cells, part of the immune system, can kill cancer cells. CAR-T cells are T-cells that have been modified in the lab to home in on proteins on the surface of an individual’s cancer cells. CAR-T cells are custom-made for each patient.

Both T-cells and CAR-T cells can become “exhausted” in the hostile tumor microenvironment. Mehrotra’s lab looks at ways to boost these cells so that they can fight cancer for a longer time.

“The whole tumor microenvironment is conducive for the tumor itself, but not for the other cells which are trying to get in there,” Mehrotra said.

Just like people, cells are constantly subjected to stress — stress from biochemical reactions that have become unbalanced and mechanical stress from moving. Transient stress can be good. Stressing your muscles through exercise strengthens them, and transient stress on cells can prompt them to a response that ultimately strengthens them.

“But if this stress stays there, which it does in the tumor microenvironment, the cells are just in continuous stress, and that will then lead to a very different phenotype and death,” Mehrotra said.

However, the researchers found that treating the Golgi apparatus with hydrogen sulfide created T-cells that could take more stress.

“Hydrogen sulfide is a gaseous signaling molecule present in pretty much all mammalian cell types. Typically, it’s a byproduct of different cellular processes, but it’s actually been shown to have really important signaling roles as well,” Oberholtzer said.

“It can modify proteins through a process called sulfhydration, where it modifies cysteine residues and can change their activity.”

In this project, Oberholtzer found that this sulfhydration process, in modifying a protein called Prdx4 within the Golgi apparatus, confers protection in an oxidative setting.

“When you have the stressors that the tumor microenvironment puts on T-cells, you get a disruption, or fragmentation, of the Golgi apparatus where it essentially isn’t able to do its job. Hydrogen sulfide protects against that disruption,” Oberholtzer said.

Looking into this protective effect then led the researchers to look more closely at the Golgi apparatus by itself.

“Essentially, if you just use the Golgi apparatus as a simple marker, if T-cells have a lot of Golgi versus less, the ones that have more Golgi are much more robust at killing tumor cells and controlling tumors,” Oberholtzer explained.

Using cell sorting technology at the Flow Cytometry & Cell Sorting Shared Resource at Hollings, the researchers sorted T-cells according to the amount of Golgi they contained. The top 30% were labeled Golgi-hi and the bottom 30% were labeled Golgi-lo.

“Basically, all the cells which are expressing high Golgi have a very different phenotype. They are less exhausted, and they are much more potent in controlling tumors,” Mehrotra said.

This pre-clinical work suggests that sorting T-cells into Golgi-hi and Golgi-lo and reinfusing only the Golgi-hi cells into a patient would create a better chance of controlling the tumor.

“Right now, we’re working on doing some validation studies in the Center for Cellular Therapy to potentially be able to start a clinical trial to see if that has a translational ability as well,” Oberholtzer said.

More work is also needed to understand the role of Golgi stress when all of the organelles in a cell are under stress because of the tumor microenvironment.