3D printed neuronal networks are an important step forward in treating spinal cord injury

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3D printed live neuronal cells. Image courtesy of the University of Minnesota.

Approximately 300,000 people in the United States live with spinal cord injury (SCI), and 17,000 new cases are reported every year. With no cure, the primary treatment option for people with SCI is rehabilitation with a physical therapist combined with medications to control the pain. Given the relatively permanent nature of these injuries, a new study conducted by Dr. Michael McAlpine and Dr. Ann Parr’s groups at the University of Minnesota is particularly exciting. These scientists have developed a 3D-printing technique to generate a network of neuronal cells in the lab, which they hope will be useful to treat patients with long term SCI. This is the first instance of printing and differentiating neuronal stem cells in a lab. Let’s take a look at how they did it!

The investigators started with induced pluripotent stem cells derived from adult cells (ex. blood, skin etc…), which were then used to bioprint the neurons of interest. They not only printed neurons, but also neuronal support cells called oligodendrocytes, which are responsible for ensuring that neurons can transmit messages efficiently. The uniqueness of their approach lies in their printing process, where the cells were printed in the context of a silicone mold. The silicone “guide” promoted neuronal differentiation as well as provided a scaffold for the scientists to spatially organize the architecture of the cells they generated. Both spatial organization and the presence of the neuronal support cells is particularly important because previous studies have shown that while injecting rodents with neural stem cells has improved SCI, the longevity of these results was compromised by a lack of support system for the injected cells. Therefore, the ability to generate both a functional cell type as well as a spatially accurate structure is important to make this neuronal printing system relevant for treating patients.

To confirm that printed cells were functional, the investigators used calcium flux assays, which demonstrated that the neuronal networks generated were able to communicate with each other. Not only were the cells healthy and functional, but their viability was exceptional: 75% of the cells stayed alive, which is remarkable for cells printed in a laboratory.

While there is still a long way to go before this type of treatment can used to treat SCI in humans, the potential for helping people with long term spinal cord injury is significant. Dr. Parr states:

“We’ve found that relaying any signals across the injury could improve functions for the patients. There’s a perception that people with spinal cord injuries will only be happy if they can walk again. In reality, most want simple things like bladder control or to be able to stop uncontrollable movements of their legs. These simple improvements in function could greatly improve their lives.”

The possibility of implanted neuronal stem cells being effective to treat SCI is also being investigated with the CIRM-funded Asterias trial. To check out more information about this work, read our blog post here and the clinical trial details here.

Stem cell treatment for spinal cord injury offers improved chance of independent life for patients

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Kris Boesen, CIRM spinal cord injury clinical trial patient works to strengthen his upper body. (Photo/Greg Iger)

A spinal cord injury is devastating, changing a person’s life in a heartbeat. In the past there was little that doctors could do other than offer pain relief and physical therapy to try and regain as much muscle function as possible. That’s why the latest results from the CIRM-supported Asterias Biotherapeutics spinal cord injury trial are so encouraging.

Asterias is transplanting what they call AST-OPC1 cells into patients who have suffered injuries that left them paralyzed from the neck down.  AST-OPC1 are oligodendrocyte progenitor cells, which develop into cells that support and protect nerve cells in the central nervous system, the area damaged in spinal cord injury. It’s hoped the treatment will restore connections at the injury site, allowing patients to regain some movement and feeling.

The latest results seem to suggest they are doing just that.

In a news release, Asterias reports that of the 25 patients treated in this clinical trial none have experienced serious side effects. They also reported that magnetic resonance imaging (MRI) tests show that more than 95 percent of the patients have shown evidence of what’s called “tissue matrix” at the injury site. This is encouraging because it suggests the implanted cells are engrafting and helping prevent a cavitation, a serious process that often occurs in spinal cord injuries and can lead to permanent loss of muscle and sensory function plus chronic pain.

The study also shows that after six months:

  • 100 percent of the patients in Group 5 (who received 20 million cells) have recovered at least one motor level (for example increased ability to use their arms) on at least one side
  • Two patients in Group 5 recovered one motor level on both sides
  • Altogether four of the 25 patients have recovered two or more motor levels on at least one side.

Not surprisingly Ed Wirth, the Chief Medical Officer at Asterias, was pleased with the results:

“The results from the study remain encouraging as the six-month follow-up data continued to demonstrate a positive safety profile and show that the AST-OPC1 cells are successfully engrafting in patients.”

While none of the patients are able to walk, just regaining some use of their arms or hands can have a hugely important impact on their quality of life and their ability to lead an independent life. And, because lifetime costs of taking care of someone who is paralyzed from the neck or chest down can run as high as $5 million, anything that increases a patient’s independence can have a big impact on those costs.

The impact of this research is helping change the lives of the patients who received it. One of those patients is Jake Javier. We have blogged about Jake several times over the last two years and recently showed this video about his first year at Cal Poly and how Jake is turning what could have been a life-ending event into a life-affirming one.

 

Stem Cell Roundup: Jake Javier’s amazing spirit; TV report highlights clinic offering unproven stem cell therapies

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Jake Javier: Photo Michael Clemens, Sees the Day

In the Roundup we usually focus on studies that highlight advances in stem cell research but today we’re going to do something a little different. Instead of relying on print for our stories, we’re turning to video.

We begin with a piece about Jake Javier. Regular readers of our blog will remember that Jake is the young man who broke his neck the day before he graduated high school, leaving him paralyzed from the upper chest down.

After enrolling in the CIRM-funded Asterias clinical trial, and receiving a transplant of 10 million stem cells, Jake regained enough use of his arms and hands to be able to go to Cal Poly and start his life over.

This video highlights the struggles and challenges he faced in his first year, and his extraordinary spirit in overcoming them.

(thanks to Matt Yoon and his Creative Services team at Cal Poly for this video)

Going Undercover

The second video is from the NBC7 TV station in San Diego and highlights one of the big problems in regenerative medicine today, clinics offering unproven therapies. The investigative team at NBC7 went undercover at a stem cell clinic seminar where presenters talked about “the most significant breakthrough in natural medicine” for improving mobility and reducing pain. As the reporter discovered, the reality didn’t live up to the promise.

NBC7 Investigative Report

 

Scientists repair spinal cord injuries in monkeys using human stem cells

Human neuronal stem cells extend axons (green). (Image UCSD)

An exciting development for spinal cord injury research was published this week in the journal Nature Medicine. Scientists from the University of San Diego School of Medicine transplanted human neural progenitor cells (NPCs) into rhesus monkeys that had spinal cord injuries. These cells, which are capable of turning into other cells in the brain, survived and robustly developed into nerve cells that improved the monkeys’ use of their hands and arms.

The scientists grafted 20 million human NPCs derived from embryonic stem cells into two-week-old spinal cord lesions in the monkeys. These stem cells were delivered with growth factors to improve their survival and growth. The monkeys were also treated with immunosuppressive drugs to prevent their immune system from rejecting the human cells.

After nine months, they discovered that the NPCs had developed into nerve cells within the injury site that extended past the injury into healthy tissue. These nerve extensions are called axons, which allow nerves to transmit electrical signals and instructions to other brain cells. During spinal cord injury, nerve cells and their axon extensions are damaged. Scientists have found it difficult to regenerate these damaged cells because of the inhibitory growth environment created at the injury site. You can compare it to the build-up of scar tissue after a heart attack. The heart has difficulty regenerating healthy heart muscle, which is instead replaced by fibrous scar tissue.

Excitingly, the UCSD team was able to overcome this hurdle in their current study. When they transplanted human NPCs with growth factors into the monkeys, they found that the cells were not affected by the inhibitory environment of the injury and were able to robustly develop into nerve cells and send out axon extensions.

Large numbers of human axons (green) emerge from a lesion/graft sites. Many axons travel along the interface (indicated by arrows) between spinal cord white matter (nerve fibers covered with myelin) and spinal cord gray matter (nerves without the whitish myelin sheathing). Image courtesy of Mark Tuszynski, UC San Diego School of Medicine.

The senior scientist on the study, Dr. Mark Tuszynski, explained how their findings in a large animal model are a huge step forward for the field in a UCSD Health news release:

“While there was real progress in research using small animal models, there were also enormous uncertainties that we felt could only be addressed by progressing to models more like humans before we conduct trials with people. We discovered that the grafting methods used with rodents didn’t work in larger, non-human primates. There were critical issues of scale, immunosuppression, timing and other features of methodology that had to be altered or invented. Had we attempted human transplantation without prior large animal testing, there would have been substantial risk of clinical trial failure, not because neural stem cells failed to reach their biological potential but because of things we did not know in terms of grafting and supporting the grafted cells.”

Dr. Tuszynski is a CIRM-grantee whose earlier research involved optimizing stem cell treatments for rodent models of spinal cord injury. We’ve blogged about that research previously on the Stem Cellar here and here.

Tuszynski recently was awarded a CIRM discovery stage research grant to develop a candidate human neural stem cell line that is optimized to repair the injured spinal cord and can be used in human clinical trials. He expressed cautious optimism about the future of this treatment for spinal cord injury patients emphasizing the need for patience and more research before arriving at clinical trials:

“We seem to have overcome some major barriers, including the inhibitory nature of adult myelin against axon growth. Our work has taught us that stem cells will take a long time to mature after transplantation to an injury site, and that patience will be required when moving to humans. Still, the growth we observe from these cells is remarkable — and unlike anything I thought possible even ten years ago. There is clearly significant potential here that we hope will benefit humans with spinal cord injury.”


Related Links:

How a stem cell transplant may help transform Lucas Lindner’s life

Lucas Lidner was left paralyzed below the chin after a truck accident last May.  Photo: Fox6Now, Milwaukee

On a Sunday morning in early 2016, Lucas Lindner was driving to get some donuts for his grandmother. A deer jumped in front of his truck. Lucas swerved to avoid it and crashed, suffering a severe spinal cord injury that left him paralyzed from the neck down.

Lucas took part in a CIRM-funded clinical trial, becoming just the second person to get 10 million stem cells transplanted into his neck. Since then he has regained some use of his arms and hands. While some patients with spinal cord injuries do experience what is called “spontaneous” recovery, Lucas was not the only person in the trial who experienced an improvement. Asterias Biotherapeutics, the company behind the clinical trial, reported that four of the six patients in the trial “have recovered 2 or more motor levels on at least one side through 12 months, which is more than double the rates of recovery seen in both matched historical controls and published data in a similar population.”

Lucas says his improvement has changed his life.

“I was pretty skeptical after the accident, on being able to do anything, on what was going to happen. But regaining hand function alone gave me everything I pretty much needed or wanted back.”

Lucas can now type 40 words a minute, use a soldering iron and touch his pinkie to his thumb, something he couldn’t do after the accident.

In August of last year Lucas did something else he never imagined he would be able to do, he threw out the first pitch at a Milwaukee Brewers baseball game. At the time, he said “I’m blown away by the fact that I can pitch a ball again.”

Lucas Lindner at the Milwaukee Brewers baseball game.

Now Lucas has his sights set on something even more ambitious. He is going back to school to study IT.

“When I was in 3rd grade a teacher asked what I want to be and I said a neuro-computational engineer. Everyone laughed at me because no one knew what that meant. Now, after what happened to me, I want to be part of advancing the science, helping make injuries like mine a thing of the past.”

Even though he was one of the first people to take part in this clinical trial, Lucas doesn’t think of himself as a pioneer.

“The real pioneers are the scientists who came up with this therapy, who do it because they love it.”


You can read more about Lucas and other patients who’ve participated in CIRM-funded clinical trials in CIRM’s 2017 Annual Report on our website

For more about Lucas and his story, watch this video below from Asterias.

Positive update on Asterias’ SCiStar study for spinal cord injury at TMM 2017

This guest blog is reposted with permission from Signals Blog, published by the Center for Commercialization of Regenerative Medicine (CCRM) in Canada.

With the extensive exploitation of regenerative medicine through the marketing and selling of unapproved stem cell “therapies” online, it was refreshing to hear an update about clinical trials for a legitimate stem cell therapy at the Till & McCulloch Meetings (TMM) in Canada earlier this month.

Dr. Jane Lebkowski, of Asterias, speaking at TMM 2017

Dr. Jane Lebkowski, President of R&D and Chief Scientific Officer at Asterias Biotherapeutics Inc. shared updates from their SCiStar study. This California-based company is currently in an open-label, single-arm Phase 1/2a clinical trial for testing the safety and efficacy of treating several types of spinal cord injuries (SCI) with AST-OPC1s – a type of brain cell called an oligodendrocyte progenitor cell, which they derived from pluripotent stem cells. Earlier this year they reported promising safety results in their first two cohorts of patients and clearance to proceed into additional patients.

Asterias uses a cryopreserved human ESC (embryonic stem cell) line to derive their AST-OPC1s, which they report are a non-homogenous population containing mostly OPCs and some neural progenitor cells. Importantly, they do not observe evidence that any ESCs remain in their differentiated cultures.

Their clinical trial is operating off the heels of extensive nonclinical safety and efficacy studies in over 28 different animal studies in >3,000 rodents and pigs with a unilateral contusion SCI model, as well as data from the first ever human clinical trial with human ESC-derived products previously conducted by Geron.

In their last non-clinical animal model studies of cervical (neck) and thoracic (back) SCI, Asterias showed that as long as they inject cells within the first 30 days of injury they see a persistent reduction in cavity formation at the injury site. They also saw myelination (growth of a protective, insulating sheath around nerve extensions) of nerve cells when AST-OPC1s were injected into myelin-free Shiverer mice, and increased vascularization (blood vessel growth) of injured tissue that persists to nine months post-transplantation. They also have in vitro data to suggest that the injected cells can secrete neurotrophic factors. Importantly, they saw behavioural improvements in their animal models that include “increases in running speed, right forelimb stride length, right forelimb maximal longitudinal deviation, and right rear stride frequency.”

In her talk at TMM, Dr. Lebkowski gave some exciting details about the company’s most recent clinical study. They’ve been delivering their AST-OPC1s to 18-69 year-old patients with C4-C7 spinal cord injury at multiple doses: a low dose of about two million cells and medium at 10 million cells. They give a single injection of either two million, 10 million, or 20 million AST-OPC1s within 21 to 42 days of injury. They have results from patients in the first two cohorts so far, and reported that both two and 10 million cell doses appeared safe 12 months after administration.

Excitingly, patients who received 10 million cells showed signs of functional improvements (in their movement) that have so far persisted up to 12 months after the injection – an improvement of 12.3% on their motor test, equivalent to two full motor scores. This translates to increased arm and hand function and improved independence in activities of daily living at 12 months. Given that these patients were requiring over six hours of home care a day, even small improvements in motor function can have huge impact on their quality of life and independence.

The research community is still waiting to hear preliminary results from the third cohort of patients who received 20 million cells. Asterias is currently recruiting more patients, including those with incomplete spinal cord injury. These studies will be used to inform a larger, double-blind controlled clinical trial that will include more extensive tests of the functional and physiological effects of injecting AST-OPC1s.

This promising work has not been an easy road. It has taken over a decade of thorough and challenging research. The current work was made possible by a $14.3 million investment from the California Institute for Regenerative Medicine, and Dr. Lebkowski estimates that they have spent over $125 million U.S. for this trial. While Asterias covers non-routine medical costs for the patients who enroll, it will take time and more support from government institutions to further test this treatment and, if proven safe and effective, make it financially accessible to all eligible patients.

Returning to my first point about unapproved stem cell therapies, please engage in conversations about “hype and hope” of stem cell therapies with members of the general public, and encourage them to ask their family health team and a scientist before enrolling in any clinical trials advertised online. There are other ways you can keep our industry “honest” here. For more plain language resources on the current status of stem cell therapies, please see here and here.


Samantha Yammine

Samantha is a PhD Candidate studying neural stem cell biology in Dr. Derek van der Kooy’s lab at the University of Toronto. She is also an avid science communicator who uses social media to make science more accessible to everyone. For your daily dose of the fun and trendy side of science, find her online as @SamanthaZY on Twitter and @Science.Sam on Instagram. 

Stanford scientists are growing brain stem cells in bulk using 3D hydrogels

This blog is the final installment in our #MonthofCIRM series. Be sure to check out our other blogs highlighting important advances in CIRM-funded research and initiatives.

Neural stem cells from the brain have promising potential as cell-based therapies for treating neurological disorders such as Alzheimer’s disease, Parkinson’s, and spinal cord injury. A limiting factor preventing these brain stem cells from reaching the clinic is quantity. Scientists have a difficult time growing large populations of brain stem cells in an efficient, cost-effective manner while also maintaining the cells in a stem cell state (a condition referred to as “stemness”).

CIRM-funded scientists from Stanford University are working on a solution to this problem. Dr. Sarah Heilshorn, an associate professor of Materials Science and Engineering at Stanford, and her team are engineering 3D hydrogel technologies to make it easier and cheaper to expand high-quality neural stem cells (NSCs) for clinical applications. Their research was published yesterday in the journal Nature Materials.

Stem Cells in 3D

Similar to how moviegoers prefer to watch the latest Star Wars installment in 3D, compared to the regular screen, scientists are turning to 3D materials called hydrogels to grow large numbers of stem cells. Such an environment offers more space for the stem cells to proliferate and expand their numbers while keeping them happy in their stem cell state.

To find the ideal conditions to grow NSCs in 3D, Heilshorn’s team tested two important properties of hydrogels: stiffness and degradability (or how easy it is to remodel the structure of the hydrogel material). They designed a range of hydrogels, made from proteins with elastic qualities, that varied in these two properties. Interestingly, they found that the stiffness of the material did not have a profound effect on the “stemness” of NSCs. This result contrasts with other types of adult stem cells like muscle stem cells, which quickly differentiate into mature muscle cells when exposed to stiffer materials.

On the other hand, the researchers found that it was crucial for the NSCs to be able to remodel their 3D environment. NSCs maintained their stemness by secreting enzymes that broke down and rearranged the molecules in the hydrogels. If this enzymatic activity was blocked, or if the cells were grown in hydrogels that couldn’t be remodeled easily, NSCs lost their stemness and stopped proliferating. The team tested two other hydrogel materials and found the same results. As long as the NSCs were in a 3D environment they could remodel, they were able to maintain their stemness.

NSCs maintain their stemness in hydrogels that can be remodeled easily. Nestin (green) and Sox2 (red) are markers that indicate “high-quality” NSCs. (Image courtesy of Chris Madl, Stanford)

Caption: NSCs maintain their stemness in hydrogels that can be remodeled easily. Nestin (green) and Sox2 (red) are markers that indicate “high-quality” NSCs. (Images courtesy of Chris Madl)

Christopher Madl, a PhD student in the Heilshorn lab and the first author on the study, explained how remodeling their 3D environment allows NSCs to grow robustly in an interview with the Stem Cellar:

Chris Madl

“In this study, we identified that the ability of the neural stem cells to dynamically remodel the material was critical to maintaining the correct stem cell state. Being able to remodel (or rearrange) the material permitted the cells to contact each other.  This cell-cell contact is responsible for maintaining signals that allow the stem cells to stay in a stem-like state. Our findings allow expansion of neural stem cells from relatively low-density cultures (aiding scale-up) without the use of expensive chemicals that would otherwise be required to maintain the correct stem cell behavior (potentially decreasing cost).”

To 3D and Beyond

When asked what’s next on the research horizon, Heilshorn said two things:

Sarah Heilshorn

“First, we want to see if other stem cell types – for example, pluripotent stem cells – are also sensitive to the “remodel-ability” of materials. Second, we plan to use our discovery to create a low-cost, reproducible material for efficient expansion of stem cells for clinical applications. In particular, we’d like to explore the use of a single material platform that is injectable, so that the same material could be used to expand the stem cells and then transplant them.”

Heilshorn is planning to apply the latter idea to advance another study that her team is currently working on. The research, which is funded by a CIRM Tools and Technologies grant, aims to develop injectable hydrogels containing NSCs derived from human induced pluripotent stem cells to treat mice, and hopefully one day humans, with spinal cord injury. Heilshorn explained,

“In our CIRM-funded studies, we learned a lot about how neural stem cells interact with materials. This lead us to realize that there’s another critical bottleneck that occurs even before the stage of transplantation: being able to generate a large enough number of high-quality stem cells for transplantation. We are developing materials to improve the transplantation of stem cell-derived therapies to patients with spinal cord injuries. Unfortunately, during the transplantation process, a lot of cells can get damaged. We are now creating injectable materials that prevent this cell damage during transplantation and improve the survival and engraftment of NSCs.”

An injectable material that promotes the expansion of large populations of clinical grade stem cells that can also differentiate into mature cells is highly desired by scientists pursuing the development of cell replacement therapies. Heilshorn and her team at Stanford have made significant progress on this front and are hoping that in time, this technology will prove effective enough to reach the clinic.

CIRM-Funded Clinical Trials Targeting Brain and Eye Disorders

This blog is part of our Month of CIRM series, which features our Agency’s progress towards achieving our mission to accelerate stem cell treatments to patients with unmet medical needs.

 This week, we’re highlighting CIRM-funded clinical trials to address the growing interest in our rapidly expanding clinical portfolio. Our Agency has funded a total of 40 trials since its inception. 23 of these trials were funded after the launch of our Strategic Plan in 2016, bringing us close to the half way point of our goal to fund 50 new clinical trials by 2020.

Today we are featuring CIRM-funded trials in our neurological and eye disorders portfolio.  CIRM has funded a total of nine trials targeting these disease areas, and seven of these trials are currently active. Check out the infographic below for a list of our currently active trials.

For more details about all CIRM-funded clinical trials, visit our clinical trials page and read our clinical trials brochure which provides brief overviews of each trial.

UCLA scientists begin a journey to restore the sense of touch in paralyzed patients

Yesterday, CIRM-funded scientists at UCLA published an interesting study that sheds light on the development of sensory neurons, a type of nerve cell that is damaged in patients with spinal cord injury. Their early-stage findings could potentially, down the road, lead to the development of stem cell-based treatments that rebuild the sensory nervous system in paralyzed people that have lost their sense of touch.

Dr. Samantha Butler, a CIRM grantee and professor at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, led the study, which was published in the journal eLife.

Restoring sensation

Butler and her team were interested in understanding the basic development of sensory interneurons in the spinal cord. These are nerve cells in the spinal cord that receive sensory signals from the environment outside the body (like heat, pain and touch) and relay these signals to the brain where the senses are then perceived.

Developing spinal cord injury treatments often focus on the loss of movement caused by damage to the motor neurons in the spine that control our muscles. However, the damage caused to sensory neurons in the spine can be just as debilitating to people with paralysis. Without being able to feel whether a surface is hot or cold, paralyzed patients can sustain serious burn injuries.

Butler commented in a UCLA news release that attempting to restoring sensation in paralyzed patients is just as important as restoring movement:

Samantha Butler

“The understanding of sensory interneuron development has lagged far behind that of another class of neurons—called motor neurons—which control the body’s ability to move. This lack in understanding belies the importance of sensation: it is at the core of human experience. Some patients faced with the reality of paralysis place the recovery of the sense of touch above movement.”

BMPs are important for sensory neuron development

To restore sensation in paralyzed patients, scientists need to replace the sensory neurons that are damaged in the spine. To create these neurons, Butler looked to proteins involved in the early development of the spinal cord called bone morphogenetic proteins or BMPs.

BMPs are an important family of signaling proteins that influence development of the embryo. Their signaling can determine the fate or identity of cells including cells that make up the developing spinal cord.

It was previously thought that the concentration of BMPs determined what type of sensory neuron a stem cell would develop into, but Butler’s team found the opposite in their research. By studying developing chick embryos, they discovered that the type, not the concentration, of BMP matters when determining what subtype of sensory neuron is produced. Increasing the amount of a particular BMP in the chick spinal cord only produced more of the same type of sensory interneuron rather than creating a different type.

Increasing the concentration of a certain type of BMP increases the production of the same categories of sensory interneurons (red and green). (Image credit: UCLA)

The scientists confirmed these findings using mouse embryonic stem cells grown in the lab. Interestingly a different set of BMPs were responsible for deciding sensory neuron fate in the mouse stem cell model compared to the chick embryo. But the finding that different BMPs determine sensory neuron identity was consistent.

So what and what’s next?

While this research is still in its early stages, the findings are important because they offer a better understanding of sensory neuron development in the spinal cord. This research also hints at the potential for stem cell-based therapies that replace or restore the function of sensory neurons in paralyzed patients.

Madeline Andrews, the first author of the study, concluded:

“Central nervous system injuries and diseases are particularly devastating because the brain and spinal cord are unable to regenerate. Replacing damaged tissue with sensory interneurons derived from stem cells is a promising therapeutic strategy. Our research, which provides key insights into how sensory interneurons naturally develop, gets us one step closer to that goal.”

The next stop on the team’s research journey is to understand how BMPs influence sensory neuron development in a human stem cell model. The UCLA news release gave a sneak preview of their plans in the coming years.

“Butler’s team now plans to apply their findings to human stem cells as well as drug testing platforms that target diseased sensory interneurons. They also hope to investigate the feasibility of using sensory interneurons in cellular replacement therapies that may one day restore sensation to paralyzed patients.”

Extra dose of patience needed for spinal cord injury stem cell therapies, rat study suggests

2017 has been an exciting year for Asterias Biotherapeutics’ clinical trial which is testing a stem cell-based therapy for spinal cord injury. We’ve written several stories about patients who have made remarkable recoveries after participating in the trial (here and here).

But that doesn’t mean researchers at other companies or institutes who are also investigating spinal cord injury will be closing up shop. There’s still a long way to go with the Asterias trial and there’s still a lot to be learned about the cellular and molecular mechanisms of spinal cord injury repair, which could lead to alternative options for victims. Continued studies will also provide insights on optimizing the methods and data collection used in future clinical trials.

Human neuronal stem cells extend axons (green) three months after transplantation in rat model of spinal cord injury. Image: UCSD

In fact, this week a team of UC San Diego scientists report in the Journal of Clinical Investigation that, based on brain stem cell transplant studies in a rat model of spinal cord injury, recovery continues long after the cell therapy is injected. These findings suggest that collecting clinical trial data too soon may give researchers the false impression that their therapy is not working as well as they had hoped.

In this study, funded in part by CIRM, the researchers examined brain stem cells – or neural stem cells, in lab lingo – that were derived from human embryonic stem cells. These neural stem cells (NSCs) aren’t fully matured and give rise to nerve cells as well as support cells called glia. Previous studies have shown that when NSCs are transplanted into rodent models of spinal cord injury, the cells mature into nerve cells, make connections with nerves within the animal and can help restore some limb movement.

But the timeline for the maturation of the NSCs after transplantation into the injury site wasn’t clear because most studies only measured recovery for a few weeks or months. To get a clearer picture, the UCSD team analyzed the fate and impact of human NSCs in adult rats with spinal cord injury from 1 month to 1.5 years – the longest time such an experiment has been carried out so far. The results confirmed that the transplanted NSCs did indeed survive through the 18-month time point and led to recovery of movement in the animals’ limbs.

To their surprise, the researchers found that the NSCs continued to mature and some cell types didn’t fully specialize until 6 months or even 12 months after the transplantation. This timeline suggests that although the human cells are placed into the hostile environment of an injury site in an animal model, they still follow a maturation process seen during human development.

The researchers also focused on the fate of the nerve cells’ axons, the long, thin projections that relay nerve signals and make connections with other nerve cells. Just as is seen with normal human development, these axons were very abundant early in the experiment but over several months they went through a pruning process that’s critical for healthy nerve function.

Altogether, these studies provide evidence that waiting for the clinical trial results of stem cell-based spinal cord injury therapies will require an extra dose of patience. Team lead, Dr. Mark Tuszynski, director of the UC San Diego Translational Neuroscience Institute, summed it up this way in a press release:

Mark Tuszynski, UCSD

“The bottom line is that clinical outcome measures for future trials need to be focused on long time points after grafting. Reliance on short time points for primary outcome measures may produce misleadingly negative interpretation of results. We need to take into account the prolonged developmental biology of neural stem cells. Success, it would seem, will take time.”