Grafted brain organoids provide insight into neurological disordersApril 16, 2018
LA JOLLA--(April 16, 2018) Many neurological disorders--Alzheimer's, schizophrenia, autism, even depression--have lagged behind in new therapies. Because the brain is so complex, it can be difficult to discover new drugs and even when a drug is promising in animal models, it often doesn't work for humans.
Scientists are aiming to change that with stem cell technology by taking skin cells from a patient and turning those cells into neurons. Researchers can then test new drugs and study the development of disease in these lab-grown neurons, and even test the potential to use these "personalized neurons" for tissue replacement via transplantation to cure a damaged part of the brain. However, while biologists have already had success in growing tiny, stem-cell-based brain-like "organoids" in dishes or test tubes for diagnostic and therapeutic purposes, these model systems are still a long way from representing the complexity of the brain.
Scientists from the Salk Institute report a new approach that can develop more sophisticated organoid models by ensuring they receive sufficient oxygen and other nutrients via transplantation into rodents. The work, published in Nature Biotechnology on April 16, 2018, could yield insights into the development of cures for brain disorders; speed up the testing of drugs; and even pave the way for someday transplanting healthy populations of human cells into people's brains to replace damaged or dysfunctional tissue.
"Brain organoids are powerful tools for investigating human brain development and disorders," says senior author Rusty Gage, professor of Salk's Laboratory of Genetics. "But currently they do not fully represent native physiological environments. This work brings us one step closer to a more faithful, functional representation of the human brain and could help us design better therapies for neurological and psychiatric diseases."
Brain organoids grown in culture dishes or test tubes are structurally and functionally limited because, without a system of blood vessels, nutrients cannot reach the interior of their 3D structure. This reduces organoids' survival time and complexity, as cells cannot undergo as many divisions to increase their number or to diversify cell type. Although some researchers have attempted to address these limitations by simultaneously grafting vascular tissue onto organoids, this approach still does not fully mimic the cellular microenvironment of an actual brain.
The Gage lab sought to replicate a more supportive physiological environment by grafting human stem-cell-based organoids into a blood-vessel-rich area of the mouse brain. The grafted human organoids integrated into the host environment, formed both neurons and neuronal support cells called astrocytes, and were surveyed by immune cells. Significantly, the team saw not only native blood vessels, but vessels with blood flowing through them--a first for organoids.
"That was a big accomplishment," says Abed AlFattah Mansour, a Salk research associate and the paper's first author. "We saw infiltration of blood vessels into the organoid and supplying it with blood, which was exciting because it's perhaps the ticket for organoids' long-term survival."
As part of the study, the Salk team divided each organoid in half before transplantation, and maintained one of the halves in culture so they could directly compare the benefit of both environments. They found that the cultured halves were filled with dying cells after a few months, while the age-matched organoids in the rodents were healthy.
To find out if the transplanted organoids were functional as well as healthy, the team conducted calcium imaging tests, in which neurons produce a dye when they fire. And, indeed, the neurons within the organoids were firing in a synchronized way. Additionally, the team used a technique called optogenetics (where cells are made responsive to light) to confirm that the grafted neurons were forming connections with each other and with the host organism, which is also a first.
"This indicates that the increased blood supply not only helped the organoid to stay healthy longer, but also enabled it to achieve a level of neurological complexity that will help us better understand brain disease," says Mansour.
Human transplantation in animals has been used for decades in brain and other tissues to enhance survival and test for mature function.
"This work builds on a grafting technique I helped develop in 1984," adds Gage, who holds the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Diseases. "It is gratifying to see that it works so well with brain organoids, which have immense potential to elucidate brain function in neuropsychiatric disease."
The work was funded by the National Institutes of Health (U19 MH106434, U01 MH106882), The Paul G. Allen Family Foundation, Bob and Mary Jane Engman, The Leona M. and Harry B. Helmsley Charitable Trust Grant (2012-PG-MED), Annette C. Merle-Smith, The G. Harold and Leila Y. Mathers Foundation, JPB Foundation, Dolby Family Ventures and NIH grants (R01NS083815, R01AG047669), the CIRM Bridges to Stem Cell Research Internship Program, an EMBO Postdoctoral Long-term Fellowship (ALTF 1214-2014/European Commission FP7-Marie Curie Actions, LTFCOFUND2013 and GA-2013-609409) and the Human Frontiers Science Program (HFSP Long-Term Fellowship--LT001074/2015).
About the Salk Institute for Biological Studies:
Every cure has a starting point. The Salk Institute embodies Jonas Salk's mission to dare to make dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new understandings in neuroscience, genetics, immunology, plant biology and more. The Institute is an independent nonprofit organization and architectural landmark: small by choice, intimate by nature and fearless in the face of any challenge. Be it cancer or Alzheimer's, aging or diabetes, Salk is where cures begin. Learn more at: salk.edu.
Related Neurons Articles:
One of the big challenges in the Neuroscience field is to understand how connections and communications trigger our behavior.
In a new study published in Neuron, investigators report on a transcription factor that they have found that can help certain neurons regenerate, while simultaneously killing others.
When many individual neurons collect data, how do they reach a unanimous decision?
Individual neurons can learn not only single responses to a particular signal, but also a series of reactions at precisely timed intervals.
Putting a turbo engine into an old car gives it an entirely new life -- suddenly it can go further, faster.
Turning the theory of how the human brain perceives time on its head, a novel analysis in mice reveals that dopamine neuron activity plays a key role in judgment of time, slowing down the internal clock.
Researchers have identified a large population of previously unrecognized young neurons that migrate in the human brain during the first few months of life, contributing to the expansion of the frontal lobe, a region important for social behavior and executive function.
For decades, scientists have struggled to develop a comprehensive census of cell types in the brain.
In the brain, patterns of neural activity are perfectly balanced.
University of Alberta researchers have developed a method of connecting neurons, using ultrashort laser pulses -- a breakthrough technique that opens the door to new medical research and treatment opportunities.
Related Neurons Reading:
The Neuron: Cell and Molecular Biology
by Irwin B. Levitan (Author), Leonard K. Kaczmarek (Author)
The Fourth Edition of The Neuron provides a comprehensive first course in the cell and molecular biology of nerve cells. The book begins with properties of the many newly discovered ion channels that have emerged through mapping of the genome. These channels shape the way a single neuron generates varied patterns of electrical activity. Covered next are the molecular mechanisms that convert electrical activity into the secretion of neurotransmitter hormones at synaptic junctions between neurons. The following section examines the biochemical pathways that are linked to the action of... View Details
The Neuron: Cell and Molecular Biology
by Irwin B. Levitan (Author), Leonard K. Kaczmarek (Author)
The third edition of The Neuron provides a comprehensive first course in the cell and molecular biology of nerve cells. The first part of the book covers the properties of the many ion channels that shape the way a single neuron generates varied patterns of electrical activity, as well as the molecular mechanisms that convert electrical activity into the secretion of neurotransmitter hormones at synaptic junctions between neurons. The second part covers the biochemical pathways that are linked to the action of neurotransmitters and can alter the cellular properties of neurons or... View Details
The 7 Secrets of Neuron Leadership: What Top Military Commanders, Neuroscientists, and the Ancient Greeks Teach Us about Inspiring Teams
by W. Craig Reed (Author), Gordon R. England (Foreword)
Leadership techniques backed by the world's most effective teams
The 7 Secrets of Neuron Leadership offers a diverse collection of wisdom and practical knowledge to help you build and lead your most effective team yet. Written by a former U.S. Navy diver, this book draws from the author's experiences and beyond to reveal key truths about the nature of teamwork, and expose the core of effective team leadership. You'll go back to ancient Greece to discover the nine personality types and the seven types of love that form the foundation of human interaction, and learn how... View Details
Molecular and Cellular Physiology of Neurons, Second Edition
by Gordon L. Fain (Author), Margery J. Fain (Illustrator), Thomas O'Dell (Illustrator)
Molecular and Cellular Physiology of Neurons, Second Edition is a comprehensive, up-to-date introduction to essential concepts of cellular neuroscience. Emphasizing experimental approaches and recent discoveries, it provides an in-depth look at the structure and function of nerve cells, from protein receptors and synapses to the biochemical processes that drive the mammalian nervous system.
Starting with the basics of electrical current flow across cell membranes, Gordon Fain covers voltage gating and receptor activation in the context of... View Details
From Neurons to Neighborhoods : The Science of Early Childhood Development
by Committee on Integrating the Science of Early Childhood Development (Author), Youth, and Families Board on Children (Author), National Research Council (Author), Committee on Integrating the Science of Early Childhood Development (Author), Jack P. Shonkoff (Editor), Deborah A. Phillips (Editor)
How we raise young children is one of today's most highly personalized and sharply politicized issues, in part because each of us can claim some level of "expertise." The debate has intensified as discoveries about our development-in the womb and in the first months and years-have reached the popular media.
How can we use our burgeoning knowledge to assure the well-being of all young children, for their own sake as well as for the sake of our nation? Drawing from new findings, this book presents important conclusions about nature-versus-nurture, the impact of being born into a... View Details
From Neuron to Brain
by John G. Nicholls (Author), A. Robert Martin (Author), David A. Brown (Author), Mathew E. Diamond (Author), David A. Weisblat (Author), Paul A. Fuchs (Author)
From Neuron to Brain, Fifth Edition, provides a readable, up-to-date book for use in undergraduate, graduate, and medical school courses in neuroscience. As in previous editions, the emphasis is on experiments made by electrical recordings, molecular and cellular biological techniques, and behavioral studies on the nervous system, from simple reflexes to cognitive functions. Lines of research are followed from the inception of an idea to new findings being made in laboratories and clinics today.
A major change is that this edition begins with the anatomy and physiology of the... View Details
From Photon to Neuron: Light, Imaging, Vision
by Philip Nelson (Author)
A richly illustrated undergraduate textbook on the physics and biology of light
Students in the physical and life sciences, and in engineering, need to know about the physics and biology of light. Recently, it has become increasingly clear that an understanding of the quantum nature of light is essential, both for the latest imaging technologies and to advance our knowledge of fundamental life processes, such as photosynthesis and human vision. From Photon to Neuron provides undergraduates with an accessible introduction to the physics of light and offers a unified view... View Details
Neuron: A Tutorial Study Guide
by Nicoladie Tam, Ph.D.
“Neuron” is a part of the college-level Principles of Biology course series and the Neuropsychopharmacology course series textbooks. It is a tutorial written in questions and answers format to describe the anatomy and physiology of the neurons in the brain.
It is a study guide with in-depth explanations. Each section is a modular unit that is self-contained for easy reading. The principles and concepts are introduced systematically so students can learn and retain the materials intuitively.
The Myth of Mirror Neurons: The Real Neuroscience of Communication and Cognition
by Gregory Hickok (Author)
An essential reconsideration of one of the most far-reaching theories in modern neuroscience and psychology.In 1992, a group of neuroscientists from Parma, Italy, reported a new class of brain cells discovered in the motor cortex of the macaque monkey. These cells, later dubbed mirror neurons, responded equally well during the monkey’s own motor actions, such as grabbing an object, and while the monkey watched someone else perform similar motor actions. Researchers speculated that the neurons allowed the monkey to understand others by simulating their actions in its... View Details
Neurons in Action 2: Tutorials and Simulations using NEURON
by John W. Moore (Author), Ann E. Stuart (Author)
Note: Purchase of Neurons in Action 2 provides the user with a 180-day online subscription.
Neurons in Action 2 is the second version of a unique software learning tool that combines hyperlinked text with NEURON simulations of laboratory experiments in neurophysiology. Version 2 features nine new tutorials introducing new channel types, single-channel simulations, and a redesigned interface. Neurons in Action's moving graphs provide insight into nerve function that is simply not possible with conventional,... View Details