The advent and evolution of stem cell technology has transformed what is understood about human biology and disease. The biomolecular characterization of stem cells, and their ability to produce virtually any cell in the body revealed new mechanisms of early human development. Beyond their contribution to basic sciences, they show significant promise in the field of regenerative medicine as a source of cells tailored to replace damaged or dysfunctional tissues.
A quick survey of the itinerary from June’s International Society for Stem Cell and Regenerative Medicine annual conference, for example, highlights efforts to apply stem cells to treat conditions such as age-related macular degeneration (AMD), diabetes, COVID-19-related acute respiratory distress syndrome, and even hair loss.
Researchers increasingly use stem cells to model neurological disorders such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS) using organoids and organs-on-a-chip. Although most translational research exploring the therapeutic potential of stem cells is at the preclinical stage, enthusiasm for neurological applications has never been higher.
“The CNS is a prime target for this type of approach, simply because there are so many unmet needs with chronic devastating diseases that lack effective treatment options,” explained Cory Nicholas, co-founder and CEO of Neurona Therapeutics. “In our opinion, the only way to effectively and completely intervene with a potential curative approach is to use regenerative stem cell technologies to rebuild those missing cells and tissues and to then replace them.”
According to Brian Culley, CEO of Lineage Cell Therapeutics, however, that use of regenerative stem cell technologies currently ranges from rigorously tested experimental and clinical systems to overt non-FDA-approved quackery.
The first step in exploring the regenerative potential of stem cells is understanding what the cells are, and how researchers are testing them.
Earlier this year, neuropharmacologists Farzane Sivandzade and Luca Cucullo from Oakland University surveyed the regenerative stem cell landscape for potential therapeutics for neurological disorders (1). Focusing their attention on four stem cell populations, embryonic (ESC), induced pluripotent (iPSC), mesenchymal (MSC), and neural (NSC), they suggested that the rationale for using a particular source depends on the desired applications and outcomes, as each cell offers individual qualities and advantages (see table, Origin stories).
ESCs and iPSCs are an attractive starting point since they are pluripotent, meaning they can differentiate to any cell in the body outside of the trophectoderm. However, their pluripotent potential can also cause the formation of tumors known as teratomas when injected directly into an organism, making their differentiated counterparts such as NSCs and MSCs more appealing.
Choosing between ESCs and iPSCs as a starting point to make those more differentiated cells comes with its own set of complications.
Sivandzade and Cucullo noted a major knock against ESCs is ethical questions about the source material based on the erroneous belief that these cells come from aborted fetuses. Culley sees things differently, stating that Lineage Cell Therapeutics derives its products from one of the 400+ cell lines cleared for federal funding by the NIH. More than two decades old and well characterized, the cell lines were donated from supernumerary in vitro fertilization procedures.
iPSC technologies circumvent these ethical concerns. Nearly any somatic cell can be “reprogrammed” into pluripotent stem cells allowing researchers to examine the potential therapeutic benefits of a pluripotent cell line and its diverse set of differentiation products. This system founded a new field of researchers pursuing iPSCs as therapeutic starting materials.
However, Culley suggested that iPSCs don’t fully recapitulate ESC pluripotency. ESCs express key pluripotency genes that are required for their pluripotent potential and self-renewal capacity. As they differentiate, these genes are turned off, and genes specific to the differentiated lineage are turned on. Although iPSCs express these pluripotency genes, researchers observed low level expression of some genes only meant to be expressed in differentiated cells causing some, like Culley, to question their full pluripotent potential.
For this reason and others, Lineage Cell Therapeutics starts with ESCs rather than iPSCs to treat spinal cord injury. Researchers at the company differentiate ESCs into a specific form: a neural cell called oligodendrocyte precursor cells (OPCs). In vivo, these cells are responsible for the production of myelin, the insulating material that wraps around and protects axons, helping those cells transmit electrical impulses along the spine.
Many labs tried to repair spinal cord injury by regrowing axons, including using small molecules to stimulate axonal growth, or antibodies to block the inhibitors of axonal development. Generating axons is not enough, however, to create a functional network.
“There's this mechanism by which nerves that wire together will fire together,” Culley explained. “If you just create a bunch of wires and throw it in a pile with some batteries, you don't get directional movement out the other end of it. You just have a bunch of static electricity zapping around.”
This is where the myelin sheath comes in, providing the insulation that prevents random firing. Using OPCs as a therapeutic material can revive the functional network by regenerating the myelin sheath, targeting the broken network rather than one dysfunctional cell type.
Clinical results are encouraging, Culley said, suggesting that about one-third of patients see significant benefits from therapy.
For example, researchers from Asterias Biotherapeutics (now part of Lineage Cell Therapeutics) conducting a Phase 1/2a clinical trial of OPCs to treat spinal cord injury known as SciStar noted that 96% of patients with cystic cavitation (a hole in the spinal cord) saw complete lesion repair 12 months after treatment. The topline data announced in 2019 also showed that 96% of patients reported motor function improvements of one or more levels.
Although the company did not describe the specific improvements of each patient in the study, they gave the example of arm movements that allowed the patient to eat or adjust themselves with limited or no assistance. A patient who had been paralyzed from the neck down, however, threw out the first pitch at a Major League Baseball game one year after OPC treatment.
Neurona Therapeutics turned to iPSCs rather than ESCs to develop allogenic cell-based therapies for epilepsy, but, like Lineage Cell Therapeutics, also focused on repairing the broken neural circuit in these patients.
“We didn't just want to replace the cell types,” he explained. Rather, they targeted the interplay between excitatory and inhibitory neurons.
In epilepsy, there is an imbalance between the excitatory and inhibitory activity in the brain’s wiring, leaning toward a state of hyperexcitability. Thus, the company searched for a cell therapy that could target those local networks and rebalance, repair, and restore them.
“The main inhibitory neurotransmitter in the nervous system is GABA,” Nicholas continued. “So, we wanted to develop an inhibitory GABAergic neuron that would synaptically integrate and restore the missing inhibitory tone to the focal epileptic neural network.”
They focused on a specialized subset of neurons called interneurons, which relay signals between sensory and spinal neurons. However, interneurons can be inhibitory or excitatory depending on what part of the brain they are derived from.
Neurona Therapeutics’ researchers spent the last six years finding the right protocol to differentiate iPSCs into these rare, inhibitory interneurons. The key is to differentiate iPSCS into medial ganglionic eminence (MGE) progenitors first as interneurons from the MGE in vivo are inhibitory. The result is a step-wise process from iPSCs to neural progenitors to MGE progenitors to interneurons that, when injected into the brains of mice, not only improved brain pathology, but also suppressed focal seizure frequency.
In June, the company presented its clinical development plans for NRTX-1001, their lead interneuron product, at the Antiepileptic Drug and Device Trials meeting. The first-in-human effort will be an open-label, dose-escalation study of safety and preliminary efficacy in up to 15 adults with chronic mesial temporal lobe epilepsy. They also plan to file an investigational new drug application with the FDA to initiate a Phase 1/2a clinical trial in subjects with drug-resistant focal epilepsy.
Clinicians and researchers may be concerned, however, about what happens if something goes wrong with the injected cells. The current treatments for drug-resistant focal onset epilepsy help address that concern, explained Nicholas.
For the NRTX-001 clinical trial, researchers will recruit patients that would otherwise require surgery to remove the seizure-prone area. Although the surgeries can be curative, they are also tissue-destructive and can result in irreversible neurocognitive effects, such as memory impairment. In the event that NRTX-001 has unforeseen side effects, however, surgery is still an option for these patients, and clinicians could remove both the cell therapy and the surrounding tissue using a lobectomy.
“Of course, we hope that that never happens and that the cells are safe and effective, in line with our preclinical testing,” Nicholas added. “Once proven to be safe, we would like to eventually be able to offer the cell therapy to people with drug-resistant focal seizures who are not eligible for lobectomy or ablation surgery.”
Another company working with pluripotent stem cells (ESCs and iPSCs) is BlueRock Therapeutics, developing dopaminergic neurons (DA01) to treat Parkinson’s disease, a technology they licensed from Lorenz Studer, Viviane Tabar and colleagues at Memorial Sloan Kettering Cancer Center (MSKCC).
Although efforts to increase dopamine levels in the brain using dopamine precursors like Levodopa help alleviate some symptoms in people with Parkinson’s disease, the treatment does not reverse the loss of dopaminergic neurons as the disease progresses.
In a report published in February in Cell Stem Cell, Tabar and colleagues described their efforts to revamp their DA01 differentiation protocols to better comply with FDA-required conditions for human trials (2). They performed viability and biodistribution studies in mice, showing that the cells engrafted into the surrounding brain tissue and remained confined to the brain rather than spreading to other tissues in the body.
In the same study, they also examined the efficacy of DA01 by injecting the dopaminergic neurons into the brains of rats with chemically induced Parkinsonism. Over an eight-month period, the researchers saw rescue of motor deficits compared to rats receiving vehicle only.
In June, BlueRock Therapeutics announced the dosing of the first patient in its open-label Phase 1 clinical trial of DA01 in a patient with advanced Parkinson’s disease. The researchers aim to enroll ten subjects and examine the safety and tolerability of DA01 cell transplantation at one-year post-transplant. Secondary endpoints will look at cell survival and motor deficit changes at one- and two-years post-transplant.
Whereas each of these organizations view stem cells as a starting point from which to differentiate adult cells, other groups are interested in using actual stem cells isolated from individual patients as the therapy.
Many developing therapies using adult cells differentiated from iPSCs or ESCs are allogeneic, with cells derived from lines, and therefore require some degree of immunosuppression. Using stem cells from patients avoids the need for immunosuppression giving these therapies an edge.
BrainStorm Cell Therapeutics and its NurOwn programs aim to develop autologous MSC-derived therapies to treat ALS and progressive multiple sclerosis (MS).
To generate NurOwn cells, researchers isolate MSCs from a patient’s bone marrow and modify them to increase their ability to produce and carry repair molecules that provide a supportive and rejuvenating environment for damaged and dysfunctional neurons like neurotrophic factors (NTFs; molecules that support neuronal function) and other repair molecules that provide a supportive and rejuvenating environment for damaged and dysfunctional neurons.
“This is not a cell replacement strategy,” said Ralph Kern, company president and CMO. “It's a good delivery vehicle that at the same time, has properties that enhance [NurOwn cell] activity.”
For example, the neurotrophic factors and other molecules carried by the NurOwn cells modulate both the innate and adaptive immune systems, whether through their impact on cytokines, microglia and macrophages, or through the upregulation of regulatory T and B cells, respectively. In different ways, each of these immune systems affect the pathology of ALS and MS.
For example, ALS patients have higher numbers of activated microglia, reactive astrocytes, dendritic cells and CD8+ T cells, which contribute to the progression of neuroinflammation and motor neuron injury. Similarly, people with MS have an immune bias toward inflammatory T cells rather than regulatory T cells and their B cells produce antibodies that damage myelin, oligodendrocytes, and other neuronal structures. Thus, it is important to downregulate these neuroinflammatory cascades to slow and possibly stop the disease pathology.
Although researchers often need to tailor cell-based treatments to address specific conditions, BrainStorm Therapeutics’ researchers can use the same process to generate NurOwn cells to treat both ALS and progressive MS. As Kern explained, this is possible because the modified MSCs can accommodate both the common and unique pathologies of the two diseases.
Where the immunomodulatory behavior of NurOwn addresses the common inflammatory components of the conditions, different signalling molecules within the cells can help revitalize or support the damaged cells of each disease.
“Vascular endothelial growth factor (VEGF) is one of the molecules that's made in higher amounts by the differentiated cell line that we've created,” Kern said. “It's very important in the survival of motor neurons, so there is a unique application of the higher levels of VEGF in ALS.”
In contrast, two other cargo proteins, leukemia inhibitory factor and hepatocyte growth factor, support remyelination and the function of oligodendrocytes, which help ensure proper axon signalling.
“Like all complex biology, nothing is ever one molecule or one pathway,” he explained. “There are some unique and some converging pathways between those diseases.”
That complexity is precisely why a stem cell-based therapy may provide a benefit against some diseases. Whereas small molecule drugs and even some biologics are designed to strike a single target or single pathway, cells can have pleiotropic effects or multiple mechanisms of action.
“The complexity of human disease will require multifaceted approaches, either combination therapies or cells that can deliver a range of solutions,” Kern explained. “We believe that we have more than one treatment delivered at the same time because the cells are able to deliver varied cargo.”
To understand this complexity, researchers at BrainStorm also conduct biomarker studies, which help them not only monitor the molecules delivered during NurOwn cell treatment, but discover what molecules are influenced by the treatment.
Kern offered the example of a molecule called osteopontin. “Osteopontin plays a role in inflammation in both ALS and progressive MS, and we've been looking at how our treatment can modify osteopontin levels in the spinal fluid in our clinical trials.”
Kern suggested that the only way to achieve precision medicine is to embrace the complexity, to analyze all the biological events, and assemble them into something meaningful.
“One of the big efforts that we're making now is to take a complex set of biomarkers, use statistical methodology, and show how the interaction of a range of biomarkers and cargo can actually help explain the outcomes in clinical trials,” he added.
Those biomarker results find rapid relevance as the NurOwn program experienced a clinical setback late last year.
In November 2020, the company reported the topline results of its Phase 3 clinical trial using NurOwn MSCs to treat patients with ALS. Treatment was well tolerated, but when it came to improving function, NurOwn only offered an incremental, insignificant functional benefit compared to placebo in both primary and secondary endpoints. The numbers were better in a pre-specified subgroup of participants with early disease, but still not statistically significant.
In announcing the findings, neurologist Merit Cudkowicz of Harvard Medical School, one of the study’s principal investigators, said, “Given the heterogeneity of ALS, it is not surprising that measurement of treatment effect may be influenced by disease severity including the behavior of disease progression rates at the lower end of the scale. In addition, NurOwn [cell treatment] was observed to have its clear intended biological effects with important changes in the pre-specified disease and drug-related biomarkers.”
To her point, CSF biomarker analysis confirmed that NurOwn cell treatment produced a statistically significant increase in neurotrophic factors as well as a reduction in neurodegenerative and neuroinflammatory biomarkers not seen with placebo, even if it was unable to provide a significant functional benefit.
It may be, Kern speculated, that the researchers selected too broad a patient population.
“We want to limit the number of patients who are so far advanced where you can't measure the response to treatment, even if there is one,” he continued. “And then finally use what's available to the best of our ability, including trying to weave back what's learned from biomarkers to explain the clinical outcomes.”
Researchers saw clearer efficacy signals in their open-label Phase 2 clinical trial of the NurOwn cell therapy in progressive MS, using a matched clinical cohort from another study as a comparator. Reporting their findings in March, investigators saw both functional and cognitive improvements in patients receiving NurOwn cell therapy both from baseline and compared to patients in the other study.
“The goal in our next study would be to see if we can confirm that there's a possibility of improving function or having a meaningful functional change in people who have progressive MS,” said Kern. “Right now, I don't believe there are any treatments that can address that.”
Whereas BrainStorm Therapeutics’ scientists harvest MSCs from the bone marrow, other groups source MSCs from more accessible tissues. For example, Pamela Shaw and colleagues at the Sheffield Institute for Translational Neuroscience (SITraN) are using MSCs from adipose tissue to treat ALS.
In June, the SITraN team published a study describing the ability of adipose-derived MSCs (AD-MSCs) from mice to protect motor neurons and reduce glial activation in vitro, and in a mouse model of familial ALS (3).
The researchers noted that following injection into the spinal canal, the AD-MSCs significantly delayed motor function decline, slowed other visible signs of disease, and improved gait compared to the mice receiving vehicle. They also found that mice receiving AD-MSCs had more motor neurons than control mice, and that treatment significantly attenuated both astroglial and microglial activation, suggesting neuroprotective and anti-inflammatory effects.
In vitro, the AD-MSCs protected motor neurons from mutant astrocyte toxicity. The AD-MSCs also induced the secretion of neurotrophic factors and inhibited release of several pro-inflammatory cytokines by mutant astrocytes in co-culture.
Having a viable cell-based therapeutic is only part of the equation, however.
As Lineage Cell Therapeutics’ Culley explained, “Administration of the cells is every bit as important to us as the cells’ activity because if you get them in the wrong place, they’re not going to do anything.”
Kern thinks that finding a way to deliver cell-based therapies for neurological disorders across the blood-brain barrier is the key to optimizing administration. The brain is protected from unwelcome toxins, pathogens, and foreign cells by a layer of endothelial cells tightly packed by a network of tight junctions. While some molecules, like lipids, can passively cross the barrier, larger molecules require active transport through selective receptors. Delivering drugs across this barrier is challenging; 98% of potential drugs for neurological disorders can’t cross the barrier.
“The answer to the optimal route of administration begins with the blood-brain barrier, and I think people have to recognize that there is no technical solution for that at hand,” said Kern
Some researchers, however, find success getting MSCs across the blood-brain barrier (BBB). For example, neuroscientist Shun Shimohama of Sapporo Medical University and colleagues demonstrated in vitro MSC transmigration across a layer of rat brain microvascular endothelial cells (4). In vivo, neuropharmacologist Yoo-Hun Suh of Seoul National University and colleagues injected fluorescently-labelled adipose-derived MSCs into the tails of wildtype and Alzheimer’s disease-model mice and showed the MSCs were able to migrate into the brain and across the BBB (5).
It could be the result of a compromised BBB, noted for conditions like traumatic brain injury, Parkinson’s disease, stroke, or brain tumors. Alternatively, the penetration could be the result of a natural ability of MSCs to split tight junctions between the endothelial cells comprising the barrier.
The ability of MSCs to not only cross the BBB, but also home to the site of injury opens the door to their systemic administration, whether by intravenous or intramuscular injection, which researchers used to deliver MSCs to treat pediatric neurological conditions like autism and cerebral palsy.
For example, neurologist Yihua An and colleagues of the General Hospital of Chinese People’s Armed Police Forces injected umbilical cord-derived MSCs into the cerebrospinal fluid (CSF) of eight sets of twins with cerebral palsy; they observed improvements in gross but not fine motor function (6). Xiang Hu and colleagues at Bieke Biotech transplanted both cord blood mononuclear cells and umbilical cord-derived MSCs using intravenous and intrathecal injection into subjects diagnosed with autism (7). When comparing cell therapy to the control group receiving rehabilitation therapy, the researchers found that cell therapy offered no safety concerns and improved autism symptoms on a number of scales.
Another administrative route to the brain with increased interest is intranasal delivery.
In March 2021, Soochow University’s Quan-Hong Ma and colleagues published their efforts to administer human NSCs intranasally into a mouse model of Alzheimer’s disease (8). They observed that the NSCs survived, migrated to the brain, and differentiated into neurons.
The researchers also noted that the transplanted NSCs reduced the number of amyloid-β plaques and signs of neuroinflammation in the mouse brains, which translated into improvements in learning and memory.
Kern worries that intranasal administration may not translate well to humans. He thinks person-to-person variation in anatomy and co-existing medical conditions might prove challenging.
Researchers at BrainStorm Therapeutics, in contrast, inject their modified NurOwn MSCs into the spinal canal (intrathecal injection), delivering the cells into the CSF which takes advantage of the natural circulatory system linking the brain and spinal cord.
“One of the advantages of doing intrathecal administration is that with each administration, you can take a sample of the spinal fluid as a measure of what's happening,” Kern explained.
Kern added that CSF sampling capability facilitates their efforts to monitor biomarkers of both disease severity and treatment efficacy offering advantages over blood samples.
“There's a long list of biomarkers that have a much better readout, better signal-to-noise in the CSF than they do in the serum,” he said. “Conditions that occur in other organs can influence what happens in the serum, but the CSF is a protected compartment.”
In other scenarios where stem cells are just the starting material and the final product is fully differentiated cells, intrathecal and intracranial delivery may be the only viable administration route.
Such is the case for Lineage Cell Therapeutics’ OPCs.
“We don't think that these cells are effective at great distances. It doesn't do me any good to inject spinal cord cells into somebody's vein and think that the myelin that's produced by those cells is going to find its way to the site of injury,” Culley explained.
Thus, Lineage Cell Therapeutics went the intrathecal route, developing what Culley described as a “huge set of scaffolding that would attach to the bed” to guide the needle into the patient’s spinal cord.
Recently, the company adjusted the formulation of their cells to facilitate a shorter thaw-and-inject cycle. The new formulation, however, increased the cells’ sensitivity to cell density, requiring larger injection volumes. The spinal cord could handle the larger volumes, according the Culley, but only at slower delivery speeds.
“If I want to use this new formulation, I need four or five minutes to get those cells into the patient because I'm adding more material,” he explained. That presents a problem because to precisely deliver the cells to the CSF and minimize any risk of spinal cord damage, the patient’s body must be perfectly still, which means they can’t even be breathing.
“I can't disconnect a patient from a respirator for four or five minutes,” Culley said. “So now, the clock is ticking.”
For Lineage Cell Therapeutics, the answer to this problem is a collaboration with Neurgain Technologies, which has developed a much simpler intrathecal delivery device that rests on the patient’s back and moves in synchrony with the patient’s breathing. By coordinating the movement of the needle and the patient, clinicians no longer must stop the patient’s breathing, facilitating safer delivery.
In June, Lineage Cell Therapeutics submitted an amended investigational new drug application to the FDA to incorporate Neurgain Technologies’ parenchymal spinal delivery system into clinical trials of OPC therapy for spinal cord injury.
Achievements like those described above suggest that the field of stem cell-based therapies is reaching a maturation point. Culley noted the enormous initial expectations of the field, recalling the widely stated belief that stem cells were going to change the world and cure every disease.
Taking a more thoughtful approach, however, Culley is confident that the field is now starting to change the promises of cell therapy into clinical reality. “I feel very privileged to be dropping into cell therapy late in my career,” he said. “I feel like I've shown up at the right time.”
Although each therapeutic product must meet rigorous standards to be approved for use in humans, the pleiotropic nature and inherent complexity of cell-based therapies sets them well apart from small molecule and even biologics as commercial products.
As Brian Culley, CEO of Lineage Cell Therapeutics, noted, small molecules obey the laws of physics. Chemical bonds form and behave in specific ways. Researchers can purify compounds via HPLC and quantify peaks on a mass or infrared spectrometer. Biologics like proteins and nucleic acids may be a bit more complex biochemically, but researchers can use similar analytical techniques to ensure quality and product homogeneity.
Cells are different, Culley added, suggesting that something as simple as pipetting speeds can alter cell behavior by affecting gene expression.
“The cells that are growing in the corner of the plate behave differently than the cells that grow in the middle of the plate,” he said. “That's why we moved into 3-dimensional cultures. We grow on microcarriers so the cells don't know if they're in a thimble or a swimming pool.”
To reduce this potential variability, explained Cory Nicholas, co-founder and CEO of Neurona Therapeutics, you need to have a consistent manufacturing process that doesn’t change once it has been validated and approved. As a personal example, he recounted his efforts at the University of California, San Francisco that led to Neurona’s product.
“When we started the company, we started over,” he said. “We didn’t want to have the baggage of the earlier stage process that would be holding us back. Start with the end in mind; a process that could be scalable, clinically compatible, and can be industrialized for the market, if it works.”
A key step in developing a process is understanding the product and its composition. Researchers want to make sure that they harness its therapeutic profile in a consistent and safe way. Consistent test results are a key part of that.
Although more often aligned with the research end of neuroscience — validating tissue models and screening drug libraries, for example — Axion Biosystems sees opportunities for its multielectrode array (MEA) platform in cell therapy development.
According to Axion Application Director Daniel Millard, “As soon as you start to think of the cell as the product, you have a few key stages where the functional assay from the Maestro technology falls into play.”
He defined these as cell characterization, optimization, and then validation and control.
“Any cell therapy begins with the pathology itself and the functional properties of the cell, often termed their critical quality attributes (CQAs),” Millard explained. “MEA can help to fill that need for characterizing a stem cell product in vitro and helping to correlate that with in vivo preclinical models.”
The primary function of a neuron is to produce action potentials, he added. So, if you’re differentiating a neuron, how do you know it’s a neuron if you’re not measuring electrical signals?
Once researchers know what they want their cells to do, he continued, they can begin to optimize that performance by tweaking growth conditions or differentiation protocols, or introducing biochemical or genetic modifications, always comparing cell activity back to those initial CQAs.
“Then, once the product requirements are set and you have a product, you start to turn the crank of manufacturing,” said Millard, continuing that you are likely going to want to continue with the same assay you used to optimize your cell product to translate those CQAs into quality control testing.
Although the goals of process analytical technology standards found in other pharmaceutical pursuits may not be possible in the cell-based therapy world — especially with autologous cell therapy, where cell sources are individualized to specific patients — an increased understanding and improved definition of CQAs, as well as improvements in technology and analytics should help to limit product heterogeneity and increase therapeutic predictability.
Embryonic stem cells (ESCs)
Induced pluripotent stem cells (iPSCs)
Mesenchymal stem cells (MSCs)
Neural stem cells (NSCs)
Adapted from Sivandzade, F.; Cucullo, L. Int J Molec Sci. 22: 2153-2174 (2021)
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- Piao, J., et al. Preclinical efficacy and safety of a human embryonic stem cell-derived midbrain dopamine progenitor product, MSK-DA01. Cell Stem Cell 28: 217-229 (2021).
- Ciervo, Y., et al. Adipose-derived stem cells protect motor neurons and reduce glial activation in both in vitro and in vivo models of ALS. Mol Ther: Meth Clin Develop. 21: 413-433 (2021).
- Matsushita, t., et al. Mesenchymal stem cells transmigrate across brain microvascular endothelial cell monolayers through transiently formed inter-endothelial gaps. Neurosci Lett. 502: 41-45 (2011).
- Kim, S., et al. The preventative and therapeutic effects of intravenous human adipose-derived stem cells in Alzheimer’s disease mice. PLoS One 7: e45757 (2012).
- Wang, X., et al. Effects of umbilical cord mesenchymal stromal cells on motor function of identical twins with cerebral palsy: Pilot study on the correlation of efficacy and hereditary factors. Cytotherapy 17: 224-231 (2015).
- Lv, Y.-T., et al. Transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in autism. J Transpl Med. 11: 196 (2013).
- Lu, M.-H., et al. Intranasal transplantation of human neural stem cells ameliorates Alzheimer’s disease-like pathology in a mouse model. Front Aging Neurosci. DOI: 10.3389/fnagi.2021.650103 (2021).