Neural stem cell transplant improves outcomes for chronic ischemic stroke at 12 months

 Your competent? doctor figured out how to use this earlier research to get you recovered, right? NO? So, YOU DON'T HAVE A FUNCTIONING STROKE DOCTOR, DO YOU?

Neural stem cells sustain natural killer cells that dictate recovery from brain inflammation January 2016 Almost a decade and your doctor is still clueless on how to get you recovered?

The latest here:

Neural stem cell transplant improves outcomes for chronic ischemic stroke at 12 months

               ByRobert Herpen, MA

Fact checked byShenaz Bagha

Key takeaways:

• At 12 months, patients demonstrated improved neurological function and better gait speed.
• All adverse events, which initially worsened from baseline, spontaneously resolved.

Transplantation of neural stem cells improved neurologic and motor function for adults with chronic ischemic stroke at 12 months, according to a study presented at the International Stroke Conference.

“There are approximately 7 million chronic stroke survivors in the United States living with severe disability and little hope for recovery,” Gary K. Steinberg, MD, PhD, founder and co-director of the Stanford Stroke Center, told Healio.

New research has determined that neural stem cell implants improve outcomes at 12 months for those suffering chronic stroke. Image: Adobe Stock

As no other treatment aside from vagus nerve stimulation exists to restore function in patients with chronic stroke, Steinberg and colleagues sought to investigate the safety and efficacy of intracerebral transplantation of NR1, human embryonic-derived neural stem cells.

Their first-in-human clinical trial, which spanned 12 months, included 18 adults who were 6 to 60 months post-ischemic subcortical middle cerebral arterial stroke and recorded a Modified Rankin Scale score of 3 or 4. All participants were transplanted with 2.5 million, 5 million, 10 million or 20 million of NR1, with the primary outcome being total adverse events at 12 months as well as change in total Fugl-Meyer motor score (FMMS, 0-100) in both upper and lower extremities compared with baseline at 12 months. Secondary outcomes included performance on a gait speed test, Barthel Index (BI), NIH Stroke Scale score (NIHSS), Fluid-attenuated inversion recovery (FLAIR) MRI, resting state fMRI and Fludeoxyglucose F 18 positron emission tomography (18F FDG PET).

Participants recorded mean increases of 12.1 points for total FMMS, 7.4 points for upper extremity FMMS, 4.7 points for lower extremity FMMS, along with mean changes of 7.7 points for BI, mean NIHSS improvement of 1.77, as well as substantial improvement in gait speed at 12 months.

Data further showed that 14 of 18 participants had a new transient FLAIR signal in premotor cortex that resolved at the 2-month mark, indicative of sustained neurologic recovery, the researchers wrote.

Steinberg and colleagues also reported improved functional sensorimotor connectivity via resting state fMRI as well as increased activity in the ipsilesional motor cortex and contralesional cerebellum confirmed via 18F FDG PET.

Adverse events such as headache, expressive aphasia and asymptomatic chronic subdural hygroma, which worsened from baseline, eventually spontaneously resolved, according to the researchers.

“Our study demonstrated that intracerebral transplantation of NR1 neural stem cells in 18 patients markedly improved neurologic function at 12 months,” Steinberg told Healio. “If confirmed in larger randomized studies, this therapy has the potential to revolutionize chronic stroke care.”

Sources/Disclosures

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Source:

Steinberg GK, et al. First-in-human phase 1/2a study of intracerebral transplantation using embryonic-derived neural stem cells (NR1) for chronic ischemic stroke:12 months outcomes. Presented at: International Stroke Conference; Feb. 5-7, 2025; Los Angeles.

Disclosures: Steinberg reports acting as a consultant for Recursion, Surgical Theater, Zeiss and previously for SanBio; and receiving royalties for or as patent beneficiary of Peter Lazic. Please see the study for all other authors’ relevant financial disclosures.        

Stem Cells in the Brain Use Childlike Signals to Trigger Regeneration

 How will your competent? doctor use this to ENSURE 100% RECOVERY? Oh, your doctor has NO plans for that! So, you DON'T have a functioning stroke doctor, do you?

Stem Cells in the Brain Use Childlike Signals to Trigger Regeneration

Summary: Scientists have discovered that neural stem cells (NSCs) receive constant feedback from their daughter cells, influencing whether they remain dormant or activate to form new neurons and glia. This parent-child relationship helps regulate brain regeneration and repair.

The study also reveals that calcium signaling plays a key role in how NSCs decode multiple signals from their environment. If NSCs produce only a few daughter cells, they activate; if they produce many, they stay dormant.

These findings challenge previous assumptions that NSCs function independently and open new avenues for treating neurodevelopmental disorders. Future research will explore how these processes change in aging and disease.

Key Facts:

• Neural Stem Cell Feedback: NSCs stay dormant or activate based on signals from their own daughter cells.
• Calcium’s Role: Calcium signaling enables NSCs to integrate and decode multiple brain signals.
• Therapeutic Potential: Understanding NSC activation could lead to treatments for neurological disorders and brain injury repair.

Source: University of Ottawa

A University of Ottawa neuroscientist has led a Canadian research team to reveal important new insights into the activation dynamics of neural stem cells (NSCs). These are the stem cells that build our central nervous systems and the self-renewing.

The collaborative team led by the University of Ottawa’s Dr. Armen Saghatelyan aimed to shed light on how neural stem cells integrate a multitude of signals from different cell types in the brain – and how they decode these signals.

These are big questions because how NSCs react to signals in their cellular environment controls whether they remain in their dormant, non-dividing state known as “quiescence” or if they get activated to grow and divide, generating new neurons and glia in the process.

In a nutshell, the research team found that a low number of daughter cells leads to activation of neural stem cells, while a large number of offspring keeps them in their typical state of quiescence in the adult brain. Credit: Neuroscience News

The reported findings, published today in Cell Stem Cell, will certainly be of deep interest to scientists studying a range of adult neurological diseases and aging. In the neural landscape, rousing NSCs from dormancy, where they conserve resources and energy, is key for neural regeneration and brain injury repair.

“These data make it possible to understand better how NSCs can be activated to generate more neurons and glia in order to counteract different neurological disorders and aging. We are currently studying NSCs’ responses for some of these conditions,” says Dr. Saghatelyan, Canada Research Chair in Postnatal Neurogenesis and the new publication’s senior author. (Neurogenesis is the process by which new neurons are formed in the brain.)

Cellular “parent-child” relationship

One avenue of new insight focuses on how stem cells wrap around progeny called “daughter” cells – genetically identical cells created after a parent cell divides. 

The team discovered that neural stem cells are in fact receiving constant feedback from their chatty daughter cells. Dr. Saghatelyan likens this to a “parent-child relationship” in which the parent is closely attuned to their child’s feedback.

“Many parents will relate to this since parents like to receive news, or feedback, from their children. Based on this feedback, the parents will either stay reassured that everything is going well or take an action,” he says, comparing this dynamic to the cellular state of quiescence or activation.

Revealing this hidden mechanism is a major finding because it provides an entirely new framework for how to understand this cellular relationship in the human brain.

“Until now it was thought that NSCs only generate progeny and that there is no interaction between them,” Dr. Saghatelyan says.

“But our work challenged this notion and showed that there is tight structuro-functional interaction between NSCs and their progeny – and that the number of progeny or the efficiency of progeny-NSC interaction determines whether neural stem cells stay quiescent or get activated to generate neurons and glia.”

In a nutshell, the research team found that a low number of daughter cells leads to activation of neural stem cells, while a large number of offspring keeps them in their typical state of quiescence in the adult brain.

Further, the new study advances our understanding of how NSCs integrate and decode a multitude of signals in space and time. Dr. Saghatelyan says the research unveils for the first time that “calcium signaling in NSCs allows for integration and decoding of all these signals.”

Informing future therapeutics

These new windows of understanding into how NSCs decode signals and how their activation is triggered offers strong potential for informing any future treatments for human neurodevelopmental disorders. 

Indeed, advancing this potential is the next step for the research collaborators as they explore questions suggested by this work.

“We are now exploring how interactions of NSCs with different cell types in their micro-environment is affected in different physiological and pathological conditions as well as in healthy aging,” says Dr. Saghatelyan, whose Faculty of Medicine research lab focuses on generating new knowledge to help boost neuronal regeneration.

The study – which started at Université Laval where Dr. Saghatelyan’s lab was located until 2022 – was conducted at the uOttawa Faculty of Medicine, where a cutting-edge two-photon imaging system made it possible to assess the functional activity of neural stem cells.

Single cell sequencing and spatial transcriptomics were performed by collaborators at University of Toronto and the University of British Columbia. Machine learning collaboration was performed at Université Laval.

Funding: The work was supported by the Canadian Institutes of Health Research (CIHR), the Canada Foundation for Innovation (CFI), and investments from the Canada Research Chair program.

About this genetics and neuroregeneration research news

Author: Paul Logothetis
Source: University of Ottawa
Contact: Paul Logothetis – University of Ottawa
Image: The image is credited to Neuroscience News

Original Research: Open access.
“Neural stem cell quiescence and activation dynamics are regulated by feedback input from their progeny under homeostatic and regenerative conditions” by Armen Saghatelyan et al. Cell Stem Cell

Tetrahydrofolate attenuates cognitive impairment after hemorrhagic stroke by promoting hippocampal neurogenesis via PTEN signaling

 Ask your competent? doctor WHOM EXACTLY is going to do the research on ischemic stroke!

Tetrahydrofolate attenuates cognitive impairment after hemorrhagic stroke by promoting hippocampal neurogenesis via PTEN signaling

Xuyang Zhang, Qingzhu Zhang, Qian Zhang, Haomiao Wang, Yi Yin, Huanhuan Li, Qianying Huang, Chao Guo, Jun Zhong, Tengyuan Zhou, Yujie Chen, Zhi Chen, Qiao Shan and Rong Hu

eNeuro 10 May 2024, ENEURO.0021-24.2024; DOI: https://doi.org/10.1523/ENEURO.0021-24.2024

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Abstract

Intracerebral hemorrhage (ICH), the most common subtype of hemorrhagic stroke, leads to cognitive impairment and imposes significant psychological burdens on patients. Hippocampal neurogenesis has been shown to play an essential role in cognitive function. Our previous study has shown that tetrahydrofolate (THF) promotes the proliferation of neural stem cells (NSCs). However, the effect of THF on cognition after ICH and the underlying mechanisms remain unclear. Here, we demonstrated that administration of THF could restore cognition after ICH. Using Nestin-GFP mice, we further revealed that THF enhanced the proliferation of hippocampal NSCs and neurogenesis after ICH. Mechanistically, we found that THF could prevent ICH-induced elevated level of PTEN and decreased expressions of phosphorylated AKT and mTOR. Furthermore, conditional deletion of PTEN in NSCs of hippocampus attenuated the inhibitory effect of ICH on the proliferation of NSCs and abnormal neurogenesis. Taken together, these results provide molecular insights into ICH-induced cognitive impairment and suggest translational clinical therapeutic strategy for hemorrhagic stroke.

Significance Statement Intracerebral hemorrhage (ICH) has been associated with cognitive dysfunction, yet its underlying mechanism remains elusive. Tetrahydrofolate (THF) has shown potential in promoting the proliferation of neural stem cells (NSCs), but its specific impact on cognitive recovery following ICH is still to be confirmed. Through the utilization of the Nestin-GFP genetic marker to track endogenous NSCs in mice, our study revealed that THF could regulate PTEN pathway to ameliorate cognitive impairment post-ICH by enhancing the proliferation of NSCs and sustaining neurogenesis. These findings contribute to valuable insights into the molecular mechanisms involved and suggest potential clinical applications for enhancing cognitive function recovery after ICH.

Abstract WMP109: Argonaute 2 Regulates Adult Neurogenesis and Oligodendrogenesis After Stroke

Will your competent? doctor ensure human research gets initiated? NO? Then you don't have a functioning stroke doctor, you have a dinosaur.

Abstract WMP109: Argonaute 2 Regulates Adult Neurogenesis and Oligodendrogenesis After Stroke

Xianshuang Liu,

Michael Chopp,

Xinli Wang,

Xu Cui,

Julie Landschoot-Ward,

Min Wei and

Zheng Gang Zhang

Originally published1 Feb 2024https://doi.org/10.1161/str.55.suppl_1.WMP109Stroke. 2024;55:AWMP109

Abstract

Background: Stroke-induced neurogenesis and oligodendrogenesis contribute to improvement of neurological function after stroke. However, mechanisms underlying post stroke neurogenesis and oligodendrogenesis warrant investigation. Argonaute (Ago) genes, the major components of the RNA-induced silencing complex, regulate microRNA (miRNA) function for post-transcriptional gene silencing. The present study investigated the role of neural stem cell (NSC) specific Ago2 after stroke.

Methods and Results: Compared to non-stroke NSCs, stroke significantly upregulated Ago2 expression in subventricular zone (SVZ) NSCs. Using adult male mice with conditional ablation of Ago2 in Ascl1 lineage NSCs (Ago2 cKO), we then examined NSC function in neurogenic regions of the SVZ and hippocampus. Under non-ischemic conditions, compared to wild-type littermates (WT), Ago2 cKO mice showed significantly reduced neuronal and oligodendrocyte differentiation of NSCs measured by newly generated neuroblasts (BrdU⁺/DCX⁺, 12±7/mm² cKO vs 32±11/mm² WT, n=3/group, p<0.05) in the neurogenic areas and new mature oligodendrocytes (BrdU⁺/CC1⁺, 20±4/mm² cKO vs 40±16/mm² WT) in the corpus callosum. In addition, Ago2 cKO mice exhibited the learning and memory impairments. Moreover, Ago2 cKO mice subjected to middle cerebral artery occlusion exhibited significantly reduced sensorimotor functions as measured by the adhesive test, foot-fault test, and modified neurological severity scores compared to WT ischemic mice. Mechanistically, mRNA and miRNA sequencing and bioinformatics analyses showed that ablation of NSC Ago2 deregulated many neurogenic genes involved in the sonic hedgehog (Shh), Notch and TGFβ signaling pathways, and altered Ago2-bound miRNAs that potentially target Shh (miR17-92 cluster), Notch (miR-124, miR-146a) and and TGFβ (miR-21, miR-200c) pathway genes, suggesting that Ago2 regulates neurogenesis and oligodendrogenesis via these miRNA-mRNA interactions.

Conclusions: Our data demonstrate an essential role of Ago2 in adult neurogenesis and oligodendrogenesis, and also provide potential therapeutic targets of Ago2-bound miRNAs for improvement of neurological outcomes after stroke by enhancing NSC function.

Click chemistry extracellular vesicle/peptide/chemokine nanomissiles for treating central nervous systems injuries

 Now if we only had ANY stroke leadership at all we could contact them to get this tested in humans. But nothing will occur, nobody has any intention of actually solving stroke.

Click chemistry extracellular vesicle/peptide/chemokine nanomissiles for treating central nervous systems injuries

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https://doi.org/10.1016/j.apsb.2022.06.007Get rights and content

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Abstract

Central nervous system (CNS) injuries, including stroke, traumatic brain injury, and spinal cord injury, are essential causes of death and long-term disability and difficult to cure, mainly due to the limited neuron regeneration and the formation of the glial scar. Herein, we apply extracellular vesicles (EVs) secreted by M2 microglia to improve the differentiation of neural stem cells (NSCs) at the injured site, and simultaneously modify them with the injured vascular targeting peptide (DA7R) and the stem cell recruiting factor (SDF-1) on their surface via copper-free click chemistry to recruit NSCs, inducing their neuronal differentiation, and serving as the nanomissiles at the injured site (Dual-EV). Results prove that the Dual-EV holds the ability to target human umbilical vascular endothelial cells (HUVECs), recruit NSCs, and promote the neuronal differentiation of NSCs in vitro. 10 miRNAs were found to be upregulated in Dual-M2-EVs compared to Dual-M0-EVs via bioinformatic analysis, and further NSC differentiation experiment by flow cytometry revealed that among these miRNAs, miR30b-3p, miR-222-3p, miR-129-5p, and miR-155-5p may exert effect of inducing NSC to differentiate into neurons. In vivo experiments show that Dual-EV nanomissiles achieve improved accumulation in the ischemic area of stroke model mice, potentiate NSCs recruitment, and increase neurogenesis. This work provides new insights for the treatment of neuronal regeneration after CNS injuries as well as endogenous stem cells, and the click chemistry EV/peptide/chemokine and related nanomissiles for improving human health.

Graphical abstract

Click chemistry extracellular vesicle/peptide/chemokine nanomissiles repair central nervous systems (CNS) injuries by targeting blood vessels, recruiting neural stem cells (NSCs) and inducing their differentiation into neurons.

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Neural stem cells sustain natural killer cells that dictate recovery from brain inflammation

How much brain inflammation is there post stroke? How do we harness this process?  We'll never know because we have NO stroke leadership or strategy.

Neural stem cells sustain natural killer cells that dictate recovery from brain inflammation

• Qiang Liu,
• Nader Sanai,
• Wei-Na Jin,
• Antonio La Cava,
• Luc Van Kaer
• & Fu-Dong Shi

• Affiliations
• Contributions
• Corresponding authors

Nature Neuroscience

(2016)

doi:10.1038/nn.4211

Received

05 March 2015

Accepted

27 November 2015

Published online

11 January 2016

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Abstract

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Recovery from organ-specific autoimmune diseases largely relies on the mobilization of endogenous repair mechanisms and local factors that control them. Natural killer (NK) cells are swiftly mobilized to organs targeted by autoimmunity and typically undergo numerical contraction when inflammation wanes. We report the unexpected finding that NK cells are retained in the brain subventricular zone (SVZ) during the chronic phase of multiple sclerosis in humans and its animal model in mice. These NK cells were found preferentially in close proximity to SVZ neural stem cells (NSCs) that produce interleukin-15 and sustain functionally competent NK cells. Moreover, NK cells limited the reparative capacity of NSCs following brain inflammation. These findings reveal that reciprocal interactions between NSCs and NK cells regulate neurorepair.