New stem cell therapy in animal model could eventually lead to viable treatment option
Newswise — The pivotal study was funded by the National Institute of Neurological Disorders and Stroke (R01NS125232, R01NS110387), and featured on the April Vol. 34 No.17 front cover of Advanced Functional Materials Journal.
Brain injury is the most common consequence of cardiac arrest, due to the impaired blood flow and oxygen to the brain. About 70 percent of the nearly 7 million people who suffer from cardiac arrest each year experience a long-term brain injury that leads to permanent disability.
The potential of stem cell therapy to address neurological dysfunction has long been fraught with challenges due to the harsh in vivo microenvironment of the brain; this results in poor stem cell retention and integration at the site of injuries.
Recent advances in manipulating a cell’s complex carbohydrate structure through metabolic glycoengineering, has enabled UMSOM researchers to explore the efficacy of a modified sugar molecule, known as the TProp sugar analog, to help stem cells remain more viable in the brain.
“All cells in a person’s body are enveloped in sugar molecules called 'glycans',” said Dr. Jia. “Through our previous research, we were able to find that these sugar molecules are vital to cell function. Glycoengineering has enabled us to further enhance stem cell viability so they may provide therapeutic effects for cardiac-arrest-induced brain injuries. This is a very important step forward in regenerative medicine for patients.”
In the study, researchers examined the efficacy in a rat model and compared the effects of “naïve” human neural stem cells to neural stem cells that were pretreated with the “TProp” sugar analog. The study found that stem cells pretreated with TProp, substantially improved brain function and reduced anxiety and depression-associated behaviors through various behavioral tests.
The treatment also activated the related inflammatory Wnt/β-catenin signaling pathway, which regulates critical aspects of cell function. This upregulated pathway by TProp promotes the transition of stem cells into neurons, the nerve cells responsible for sending and receiving signals from the brain.
The TProp-pretreated group also demonstrated improved synaptic plasticity, the ability of neurons to modify the strength of their connections, and reduced neuroinflammation in the central nervous system, providing a superior ability to regenerate and recover from damaged brain functions.
The results indicate that glycoengineered stem cells have the potential to promote the growth of new connections among surviving or regenerated neurons, leading to regenerated circuits in the brain.
Figure 1. Schematic of novel stem cell therapy with metabolic glycoengineering (MGE) for brain repair after cardiac arrest (CA). Conditions were characterized and optimized in vitro to modify human neural stem cells by using the TProp sugar analog (Ac5ManNTProp). The efficacy of the transplanted metabolically glycoengineered neural stem cells (MGE-NSC) for brain repair and how TProp analog affected the fate of neural stem cells were evaluated within a cardiac-arrest-induced brain injury rat model. Results indicated that MGE improved the viability and differentiation of neural stem cells, inhibited neuroinflammation, and provided neuroprotection after in vivo transplantation.
“This innovative research has been an important proof of concept study suggesting that stem cells could be used to regenerate neural connections in the brain of patients who suffer a devasting injury after cardiac arrest”, said Dean Mark T. Gladwin, MD, who is the John Z. and Akiko K. Bowers Distinguished Professor and Dean, UMSOM, and Vice President for Medical Affairs, University of Maryland, Baltimore. “Next steps for this translational application include determining the optimal delivery route and timing of metabolically glycoengineered stem cell therapy, as well as systemic evaluation on large animals before this can move into clinical studies.”
UMSOM faculty and postdoc co-authors of the paper include: Jian Du, PhD, Xiao Liu, MD, MS, Subash Marasini, PhD, Zhuoran Wang, MD, PhD, and Xiaofeng Jia, MD, MS, PhD, FCCM.
Faculty from the Department of Biomedical Engineering and Translational Cell and Tissue Engineering Center at The Johns Hopkins University School of Medicine also contributed to this research.
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Now in its third century, the University of Maryland School of Medicine was chartered in 1807 as the first public medical school in the United States. It continues today as one of the fastest growing, top-tier biomedical research enterprises in the world -- with 46 academic departments, centers, institutes, and programs, and a faculty of more than 3,000 physicians, scientists, and allied health professionals, including members of the National Academy of Medicine and the National Academy of Sciences, and a distinguished two-time winner of the Albert E. Lasker Award in Medical Research. With an operating budget of more than $1.2 billion, the School of Medicine works closely in partnership with the University of Maryland Medical Center and Medical System to provide research-intensive, academic, and clinically based care for nearly 2 million patients each year. The School of Medicine has more than $500 million in extramural funding, with most of its academic departments highly ranked among all medical schools in the nation in research funding. As one of the seven professional schools that make up the University of Maryland, Baltimore campus, the School of Medicine has a total population of nearly 9,000 faculty and staff, including 2,500 students, trainees, residents, and fellows. The School of Medicine, which ranks as the 8th highest among public medical schools in research productivity (according to the Association of American Medical Colleges profile) is an innovator in translational medicine, with 606 active patents and 52 start-up companies. In the latest U.S. News & World Report ranking of the Best Medical Schools, published in 2023, the UM School of Medicine is ranked #10 among the 92 public medical schools in the U.S., and in the top 16 percent (#32) of all 192 public and private U.S. medical schools. The School of Medicine works locally, nationally, and globally, with research and treatment facilities in 36 countries around the world. Visit medschool.umaryland.edu
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