SCCM Resource Library-Boosting Stem Cell Therapy by Metabolic Glycoengineering to Improve Outcomes After Cardiac Arrest

Video Transcription

Hello, everyone. I'm Xiaofen Jia, Professor of Neurosurgery Department, University of Maryland School of Medicine. Today, I would like to present boosting stem cell therapy  by metabolic glycoengineering to improve outcomes after cardiorest. Cardiorest has an incident of around 360,000 per year in the United States.  Ischemic brain injury after cardiorest, they cause irreversible neurological dysfunction.  The survival rate is only 10-25 percent, and the majority of the survivor are comatose. Currently, neither pharmacological intervention nor therapeutic hypothermia  can reverse neural injury caused by the cardiorest. Stem cell therapy holds significant promise in the neuronal repair after brain injury and has been demonstrated in stroke and TBI  and other disease.  We have previously shown stem cell therapy by using human neural stem cell with ICV administration three hours after cardiorest improve neurological outcomes.  Here we can see these two groups. Red one is neural stem cell group, and the blue one is control group. Left side is overall neural deficit score,  and the right side is sub-NDS score, which is coordinating behavior, which including high-level neuronal activities. The neural stem cell ICV administration  improved both overall NDS and sub-NDS compared to control group. We can see from the quantification of ischemic neuron. This one is a control group.  That one is neural stem cell therapy group, both in CH2 and the red indicated ischemic neurons. We can see human neural stem cell administration  significantly decreased the ischemic neuron in the CH2.  If we're checking the survived neuron by neuronal marker NEUN, we can see the red one is neural stem cell group significantly higher than control group in CH1, CH2, and DG.  And we're also using the human KU86 human nuclear marker. We can see the increased neuronal marker was associated with increased KU86 marker,  which indicated this improved neuronal survival was associated with human nuclear, that means indicated HNSC administration.  Well, we can see the neural stem cell has lots of functions through different mathematic mechanisms. So, for example, improve, promote the angiogenesis  and repair the neural repair mechanism stimulate. And they also will be stable, the BBB and stimulated expression secretion of growth factors.  All this comes together will help in re-establish of the neuronal network and promote the formation of the new communication channels. So, however, the stem cell therapy  is not as good as we expected, which really hinted at the clinical translation. The major reason for that is these cells after transplantation, they will go through the apoptosis,  they will have lower cell survival. And we really need to improve the cell survival and deflation to the targeted cell which we want. So, to improve really functional outcome  for the neurological disease. So, we're using a metabolic glycoengineering technique, which is a technique employing the sugar analog.  So, to introduce the functional group to the human NSC surface, which could enhance the cell adhesion and interaction with the surrounding cells.  And subsequently, that's improved the survival rates. So, we will study the first using in-vitro cell study and then we were using in-vivo study  to demonstrate the outcome both in-vitro and in-vivo. So, the in-vivo model we're using here is from the two groups. So, that is NSC and this is treated MSE, treated MSC.  So, we three hours start injecting ICV delivery for both neural stem cell treated or not treated. And yes, recorded the fourth day.  Then after that, we had a chronic behavior testing every week. And we will have a final pathological evaluation, including immunohistology at 28 days.  So, in-vitro, actually in-vitro study, we optimize the concentration and the dose. So, we could see here is the human neural stem cell  proliferation and the deflation was significantly enhanced. So, with this sugar analog treated human stem cell exhibited a much better, much mature, longer neural rates.  This is for better cell morphology.  So, in-vivo study, we transplanted this neural stem cell in two groups. One is treated neural stem cell, another is untreated neural stem cell.  So, the overall survival hours, and this is NDS, we both could be showing the treated neural stem cell had a significantly higher survival,  percentage of survival, and the overall functional outcome evaluated by NDS. And we can see from here, as demonstrated by the crestal violet staining,  we can see treated NSSC has a significantly less ischemic neuron compared to controlled untreated neural stem cells. And there's another wound healing assay  and other migration rates also indicated the cell treated with analog exhibited significantly less cell death than the control group.  So, we had chronic behaviors, and the open field test and elevated platenase and the tail suspension both show significantly improved chronic behavioral  testing in the sugar analog treated stem cell compared to controlled stem cell, untreated stem cell. We also evaluated in-vivo cell tracking and the deflation.  So, we can see the MGE technique improve the cell survival distribution. Here is a human MT, indicated the human resource of these cells, and this is the control,  and this is NSSC, this is treated, the sugar analog treated NSSC. We can see the sugar analog treated NSSC significantly enhanced the MAP and the positive  survived and the differentiated neural survival in the hippocampus.  So, our conclusion is integration of novel MGE technique to neural SC therapy, significantly enhanced the stem cell therapy, promotes neurological functional outcome,  improves long-term behavior recovery, including decreased anxious and the reduced depression-related behavior.  Thank for the NIH grant support, including 2R1 and the members' hard work from my lab. Thank you.

Video Summary

Professor Xiaofen Jia from the University of Maryland School of Medicine discusses boosting stem cell therapy to improve outcomes after cardiorest, a condition with a high incidence rate in the United States. The survival rate of cardiorest is low, and current interventions cannot reverse the neural injury caused by it. Stem cell therapy has shown promise in neuronal repair after brain injury, and previous studies have shown that human neural stem cell therapy can improve neurological outcomes. However, cell survival and targeted cell deflation need improvement. Metabolic glycoengineering was used to introduce functional groups to the surface of human neural stem cells, enhancing cell adhesion and interaction, leading to improved survival rates and functional outcomes. In in-vitro and in-vivo studies, the treated neural stem cells demonstrated better proliferation, deflation, survival rates, and functional outcomes compared to the control group. The novel metabolic glycoengineering technique significantly enhances stem cell therapy and promotes improved neurological functional outcomes.

Asset Subtitle

Neuroscience, Cardiovascular, Transplant, 2022

Asset Caption

INTRODUCTION/HYPOTHESIS: Ischemic brain injury after cardiac arrest (CA) causes irreversible neurological dysfunction in over 90% of CA survivors. Current medical treatments do not effectively combat neuronal loss. Evolving neural stem cell (NSC) therapy has shown promising results on neuronal recovery. We previously reported the therapeutic effects of hNSC therapy when compared to the CA-only group. However, the low survival rate of transplanted NSCs hinders further development of the treatment. Metabolic glycoengineering (MGE) is a technique that employed sugar analogs to introduce functional groups to hNSC surface proteins to enhance cell adhesion, and, consequently, survival rates. This project evaluates the impact of MGE on hNSC therapy. METHODS: We developed the novel Ac5ManNTProp analog and optimized the treatment conditions and differentiation ability with hNSCs in vitro. 10 Wistar rats were randomly assigned hNSC and MGE-hNSCs groups (N = 5). After 7 minutes of asphyxial CA, hNSCs were administered intranasally 3 hours after CA. Neurological deficit scores (NDS) were assessed at 24, 48, 72h, and weekly after resuscitation. Open-Field, Elevated Maze, and Tail Suspension tests were performed weekly to monitor behavioral progression, and cell migration was quantified using immunohistochemistry of brain tissues. RESULTS: Ac5ManNTProp overcome the requirement for a complementary scaffold with increased potency and promoted neural differentiation in hNSCs in vitro. Compared to the hNSC group, animals in the MGE-hNSCs group had a significant improvement in neurological function by NDS, with improved grooming activity at 7 days from the Open-Field test, increased time spent in open arms at 14 days from the Elevated Maze test, and enhanced mobility at 28 days from tail Suspension test (all P < 0.05). The MGE technique improved the survival, distribution, and differentiation of transplanted hNSCs, with more neuronal survival in the hippocampus. CONCLUSIONS: Integration of novel MGE to NSC therapy significantly enhances stem cell therapy, improves neurological functional outcomes and long-term behavioral recovery, including decreased anxiety and reduced depression-related behavior. Supported in part by the NINDS R01NS110387 and NHLBI R01HL118084 (both to X Jia).

Meta Tag

Content Type Presentation

Knowledge Area Neuroscience

Knowledge Area Cardiovascular

Knowledge Area Transplant

Knowledge Level Advanced

Learning Pathway Cardiothoracic Critical Care

Membership Level Select

Tag Cerebral Ischemia

Tag Cardiac Arrest

Tag Stem Cells

Tag Biotechnology

Tag Brain Death

Tag Cardiothoracic Critical Care

Year 2022

Keywords

stem cell therapy

cardiorest

neural injury

metabolic glycoengineering

neurological functional outcomes

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