A New Approach to Studying the Human Brain
Researchers are using human tissue to study brain diseases more effectively.
JP McGinnis, Joshua Ortiz-Guzman, Sai Mallannagari, Maria Camila Guevara, Benjamin D. W. Belfort, Suyang Bao, Snigdha Srivastava, Maria Morkas, Emily Ji, Kalman A. Katlowitz, Angela Addison, Evelyne K. Tantry, Melissa M. Blessing, Carrie A. Mohila, Nisha Gadgil, Samuel G. McClugage III, David F. Bauer, William E. Whitehead, Guillermo Aldave, Omar Tanweer, Naser Jaleel, Ali Jalali, Akash J. Patel, Sameer A. Sheth, Howard L. Weiner, Shankar Gopinath, Ganesh Rao, Akdes Serin Harmanci, Daniel Curry, Benjamin R. Arenkiel
― 6 min read
Table of Contents
When it comes to studying the human brain, researchers often hit a wall. Most of the time, they have to rely on animal models to learn about brain diseases, but these studies don’t always translate well to humans. It’s like trying to learn how to ride a bike by watching a hamster in a wheel: it might be cute, but it's not exactly the same experience. That’s why there's a growing push for using human-based models to better understand how the brain works, especially when it comes to tough neurological diseases.
One exciting development in this field is the use of Cerebral Organoids. Think of them like miniature brains grown in a lab. They give scientists a chance to study human brain cells in a more relevant setting. Unfortunately, current versions of these organoids sometimes resemble an embryo's brain more than a fully grown human brain. This can make it hard to apply what they learn to real-world human conditions.
Enter the human brain organotypic slice model. This model allows researchers to keep real pieces of human brain tissue alive outside the body (in a lab, not a spooky mad scientist's lair). By doing this, they can study how these tissues react to different treatments or interventions over time. Ideally, these slices would maintain their original characteristics, so researchers have a more accurate picture of how they would behave in a living person.
Why Human Tissue?
Using human brain tissue is a game changer. By studying it directly, researchers can get a clearer understanding of how different types of cells in the brain work together. This is crucial for diseases like tumors, epilepsy, and other neurological disorders. The ultimate goal is to improve treatments and make clinical trials more predictive and relevant.
However, while using human tissue provides many advantages, it also comes with challenges. Not all patients undergoing surgery can provide tissue samples, and the types of diseases studied are limited to those that require surgical intervention. Still, the potential for new discoveries makes it worth the effort.
The Study Process
In a recent study, researchers collected brain tissue samples from patients undergoing surgery. The process was straightforward: get consent from the patient (or their caregivers), then collect any brain tissue that wasn't needed for diagnosis. The samples were rapidly cooled and taken to the lab for further processing.
Once in the lab, the brain tissue was carefully sectioned into slices and placed into specific culture media. These slices were treated like VIP guests, receiving daily care and maintenance to keep them alive and healthy.
After two weeks of culture, researchers were ready to analyze the samples using single-nucleus RNA sequencing. This method allowed them to examine gene expression levels for various cell types within the tissue. The aim was to see how well these cell types maintained their unique characteristics over time. If they behaved similarly to how they would in a living brain, it would indicate that the model was indeed effective.
A Peek Under the Hood
So, what exactly did the researchers find during their analysis? They looked at different cell types, such as Neurons, Astrocytes (support cells), and tumor cells, to see how their Gene Expression Profiles changed from day zero (just after surgery) to day fourteen (after two weeks in culture).
Results and Findings
The results were promising. Most cell types showed relatively high correlations between their expressions at day zero and day fourteen. This means that the cells maintained their identities over the two-week period, making the organotypic slice model a good candidate for studying brain diseases.
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Astrocytes: These support cells showed variable results. In some samples, they maintained their identity well, but in others, not so much.
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Endothelial Cells: These cells, which are part of blood vessels, did an excellent job of preserving their characteristics over time.
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Neurons: Results were mixed. While some types of neurons maintained their profiles adequately, others showed a notable decline.
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Tumor Cells: Surprisingly, tumor cells from glioblastoma and medulloblastoma samples maintained their gene expression profiles exceptionally well. This suggests that the modeling system holds promise for understanding how these aggressive cancers behave.
By comparing the day zero and day fourteen data, researchers were able to see what had changed and what had stayed the same. It’s like looking at a before-and-after photo, except instead of a new haircut, it’s about how well brain cells kept their unique characteristics over time.
Creating a Baseline
One of the key outcomes of this research was establishing a baseline for how brain cells behave outside the body. This is crucial for future studies. If researchers can understand how long different cell types can retain their identities, they can begin tweaking culture conditions to improve preservation. The more faithful the models are to real human biology, the more useful they will be for testing new therapies.
The Importance of Collaboration
Access to human brain tissue is still a challenge. Many labs may lack the ability to obtain such samples regularly. That’s why collaboration is crucial. By working together, researchers can pool their resources and knowledge to take advantage of this valuable model. Neurosurgeons, in particular, are in a unique position to lead these studies since they are often the ones doing the surgeries.
Future Directions
As researchers continue to investigate this model, there are many avenues to explore. For instance, they could look at how different types of brain diseases affect cell preservation. Could this model help researchers understand how low-grade gliomas or other specific types of tumors behave? Or how might it apply to vascular malformations or epilepsy? These questions are just the beginning.
Improving Culture Conditions
Scientists are optimistic that increasing the quality of culture conditions will lead to even better outcomes. Some researchers are focusing on using human cerebrospinal fluid (CSF) as a medium to keep tissues alive longer. By incorporating a more natural environment, they hope to improve cell survival rates and maintain even greater fidelity.
Conclusion
The human brain organotypic slice culture model represents a significant step forward in brain research. By using actual human tissue, researchers can study the complexities of the human brain in ways that traditional animal models simply can’t match.
The data is clear: brain tissue can maintain its gene expression profiles ex vivo, which could mean more reliable results for clinical trials and better therapies for patients. The future looks bright for this area of research, and who knows? Maybe one day, we’ll be able to develop not just treatments, but real fixes for the brain's greatest challenges.
So, while animal models have their place, it's time to embrace this human-centric approach. After all, who better to study the human brain than... well, humans?
Original Source
Title: Cell type transcriptional identities are maintained in cultured ex vivo human brain tissue
Abstract: It is becoming more broadly accepted that human-based models are needed to better understand the complexities of the human nervous system and its diseases. The recently developed human brain organotypic culture model is one highly promising model that requires the involvement of neurosurgeons and neurosurgical patients. Studies have investigated the electrophysiological properties of neurons in such ex vivo human tissues, but the maintenance of other cell types within explanted brain remains largely unknown. Here, using single-nucleus RNA sequencing, we systematically evaluate the transcriptional identities of the various cell types found in six patient samples after fourteen days in culture (83,501 nuclei from day 0 samples and 45,738 nuclei from day 14 samples). We used two pediatric temporal lobectomy samples, an adult frontal cortex sample, two IDH wild-type glioblastoma samples, and one medulloblastoma sample. We found remarkably high correlations of day 14 transcriptional identities to day 0 tissue, especially in tumor cells (r = 0.90 to 0.93), though microglia (r = 0.86), oligodendrocytes (r = 0.80), pericytes (r = 0.77), endothelial cells (r = 0.78), and fibroblasts (r = 0.76) showed strong preservation of their transcriptional profiles as well. Astrocytes and excitatory neurons showed more moderate preservation (r = 0.66 and 0.47, respectively). Because the main difficulty with organotypic brain cultures is the acquisition of human tissue, which is readily available to neurosurgeons, this model is easily accessible to neurosurgeon-scientists and neurosurgeons affiliated with research laboratories. Broad uptake of this more representative model should prompt advances in our understanding of many uniquely human diseases, lead to more reliable clinical trial performance, and ultimately yield better therapies for our patients.
Authors: JP McGinnis, Joshua Ortiz-Guzman, Sai Mallannagari, Maria Camila Guevara, Benjamin D. W. Belfort, Suyang Bao, Snigdha Srivastava, Maria Morkas, Emily Ji, Kalman A. Katlowitz, Angela Addison, Evelyne K. Tantry, Melissa M. Blessing, Carrie A. Mohila, Nisha Gadgil, Samuel G. McClugage III, David F. Bauer, William E. Whitehead, Guillermo Aldave, Omar Tanweer, Naser Jaleel, Ali Jalali, Akash J. Patel, Sameer A. Sheth, Howard L. Weiner, Shankar Gopinath, Ganesh Rao, Akdes Serin Harmanci, Daniel Curry, Benjamin R. Arenkiel
Last Update: 2024-12-20 00:00:00
Language: English
Source URL: https://www.biorxiv.org/content/10.1101/2024.12.19.629223
Source PDF: https://www.biorxiv.org/content/10.1101/2024.12.19.629223.full.pdf
Licence: https://creativecommons.org/licenses/by/4.0/
Changes: This summary was created with assistance from AI and may have inaccuracies. For accurate information, please refer to the original source documents linked here.
Thank you to biorxiv for use of its open access interoperability.