Weekend reads: stem cells, CRISPR, glioma, stroke, RTT & more

Venkatesh, et al. Nature 2019, Fig 2e "2e, Representative confocal image of neurons co-cultured with PSD95–RFP-labelled glioma cells. White box and arrowheads highlight region of synaptic puncta colocalization; magnified view is shown to the right. Green denotes neurofilament (axon); white denotes nestin staining (glioma cell processes); blue denotes synapsin (presynaptic puncta); red denotes PSD95–RFP staining (postsynaptic puncta). Scale bars, 10 µm (left) and 2 µm (right)."
Venkatesh, et al. Nature 2019, Fig 2e "2e, Representative confocal image of neurons co-cultured with PSD95–RFP-labelled glioma cells. White box and arrowheads highlight region of synaptic puncta colocalization; magnified view is shown to the right. Green denotes neurofilament (axon); white denotes nestin staining (glioma cell processes); blue denotes synapsin (presynaptic puncta); red denotes PSD95–RFP staining (postsynaptic puncta). Scale bars, 10 µm (left) and 2 µm (right)."
Tardigrades
Tardigrade.

Every so often I realize I’ve accumulated a bunch of tabs on my browsers of things I need to dive into as time permits, which sometimes translates into a collection of recommended reads here on The Niche. Here are some recommended recent reads in the stem cell/regenerative medicine field and childhood cancer space. It includes some great science and complex social and policy developments and opinions.

‘I just want to live’: California man pleads with scientists around the world to ‘CRISPR me’. Remarkably this STAT story centers on a tardigrade (See image) gene that a man wants introduced into himself. Resonates with Right To Try.  It’s an unsettling, but compelling story. It’s great to get more on patients’ views of things.

On that same topic, this article from Donna Young at S&P Global (and an ensuring Twitter conversation) had many of us scratching our heads last week about what was going on with what seemed to be twin Right To Try related CROs. You can see my interview with the leader of one of them, Richard Garr, here.

An NPR item Gliomas Network With Normal Brain Cells To Grow Faster on a cool new paper from Michelle Monje’s lab and papers from 2 others about how childhood brain tumors connect with the surround brain’s neural network. Brain electrical activity may in a sense “feed” the glioma in various ways including via activity-coupled secretion or pro-growth and perhaps anti-apoptotic factors. Does the tumor actual influence cognition? Does cognition influence the tumor?

Here’s the actual Nature Monje lab article.

Venkatesh, et al. Nature 2019, Fig 2e "2e, Representative confocal image of neurons co-cultured with PSD95–RFP-labelled glioma cells. White box and arrowheads highlight region of synaptic puncta colocalization; magnified view is shown to the right. Green denotes neurofilament (axon); white denotes nestin staining (glioma cell processes); blue denotes synapsin (presynaptic puncta); red denotes PSD95–RFP staining (postsynaptic puncta). Scale bars, 10 µm (left) and 2 µm (right)."
Venkatesh, et al. Nature 2019, Fig 2e “2e, Representative confocal image of neurons co-cultured with PSD95–RFP-labelled glioma cells. White box and arrowheads highlight region of synaptic puncta colocalization; magnified view is shown to the right. Green denotes neurofilament (axon); white denotes nestin staining (glioma cell processes); blue denotes synapsin (presynaptic puncta); red denotes PSD95–RFP staining (postsynaptic puncta). Scale bars, 10 µm (left) and 2 µm (right).”

See the cool Fig. 2e show connections.

Knotty Problem of Cell Reprogramming Solved. Topoisomerase role in reprogramming. Here’s the pub. I hesitated in a way to link to this because those of us at UC’s cannot access Cell Stem Cell and many other papers because of the ongoing UC-Elsevier conflict. Boo. But it’s not this particular journal’s fault.

The stem cell clinic situation in Japan and Japan’s permissive regulatory system are causing problems. From Nature: The potent effects of Japan’s stem-cell policies and an editorial A stem-cell race that no one wins. I’ll be writing more about the situation in Japan soon.

Kudos to Google for banning stem cell ads. Other tech companies should follow. From Jeremy Snyder over at STAT. My own thoughts on the Google stem cell clinic ad ban.

Intravenous Bone Marrow Mononuclear Cells for Acute Ischemic Stroke: Safety, Feasibility, and Effect Size from a Phase I Clinical Trial from the journal Stem Cells.

What are your top recent reads in these areas? Let us know in the comments.

8 Comments

  1. Speaking of stroke . . .

    https://www.ahajournals.org/doi/10.1161/STROKEAHA.119.026318

    Intravenous transfusion of allogeneic hypoxic mesenchymal cells in patients with chronic stroke suggested behavioral gains. The current study is the largest trial of intravenous MSCs in patients with chronic stroke (n=36) and the first to evaluate allogeneic MSC therapy in this population. It is also the first study to evaluate MSCs grown under hypoxic conditions favorable to cell proliferation, gene expression, cytokine production and migration.

    While patients with stroke in the chronic stage generally show significant functional decline, enrollees in the current study showed 12 months of continued functional improvements across all secondary endpoints.

    The proportion of patients achieving excellent functional outcome (Barthel index score ≥95)

    at baseline (before MSC infusion): 11% (4 patients out of 35)
    at 6 months post-infusion: 27% (9 patients out of 33) P=0.015
    at 12 months post-infusion: 35% (11 patients out of 31) P=0.010

    https://clinicaltrials.gov/ct2/show/NCT01297413

    • I saw that paper too. It definitely caught my attention in part because I’ve had some concerns about the firm in past years.
      But my quick look through the paper indicates that this looks like an IND cleared trial, the pub points out the trial’s limitations, the safety profile looks encouraging.
      I’m going to be taking a closer look at the data.

  2. Concerning the article on BM infusion in acute stroke… I do not see any methods stating how they obtained the proposed BM MSCs. They simply say ‘was obtained with a goal of 2ml/kg’. I also see nothing discussing processing of the BM in any way. Am I missing it?

    One of the biggest issues with ALL BM aspirations is the methods in which it is obtained.

    This is all I see which even mentions it. They act like an exactly understood makeup of cells was drawn and infused… but this makes absolutely no sense.

    Implementation of Intervention
    Enrollment, BM harvest, cell processing, and reinfusion of MNCs had to be completed between 24 and 72 hours of stroke symptom onset. Details of these procedures along with imaging protocols, flow cytometric analysis for cell characterization, and colony formation unit (CFU) assays have been reported 19. The volume of BM harvested was 2 ml/kg with an aim to infuse a maximum MNC dose of 10 million cells per kilogram based on preclinical data 9. The cells were infused using a peripheral intravenous line at an average rate of 1.8 ml/minute. Immunophenotype and CFU potency data are shown in Table 1.

    • In the cited reference (Savitz SI, et al. Ann Neurol 2011; 70:59). it says,

      Bone Marrow Harvest: A total of 2ml/kg bone marrow was harvested aseptically from the posterior iliac bone. Local anesthesia (1% lidocaine without epinephrine) and infusion of fentanyl and/or midazolam were used to minimize discomfort during the procedure. All patients were placed in the prone position. An 11‐gauge bone marrow needle was placed into the posterior iliac crest, and approximately 5 to 7cc was aspirated with a 20cc syringe. Additional sites on the iliac crest were chosen, and the procedure repeated. IV normal saline was administered if there were changes in hemodynamic parameters. Blood pressure (systolic, diastolic), heart rate, and arterial oxygen saturation were all measured at 5‐minute intervals intraharvest and at 15‐minute intervals postharvest for 1 hour. Hemoglobin and hematocrit were measured preharvest and at 4 and 12 hours postharvest. A 20% decrease in blood pressure unresponsive to fluids was considered an adverse event.

      There are also methods describing flow cytometry, CFU assays and infusion‐related toxicity monitoring.
      That pretty much covers it for me. What exactly are you missing that isn´t there?

    • All this should be easy enough for @admin to check since UC Irvine Dept. of Neurology is involved according to https://clinicaltrials.gov/ct2/show/NCT01297413 I’d also be interested to know if this trial was done under an FDA IND as well. It shows “STEM 101-M” as an additional ID number but it is missing this line:
      Studies a U.S. FDA-regulated Drug Product: Yes

  3. Regarding that Right To Try CRISPR story. What was not covered and not discussed with the man pleading for a therapy, is the cost of the whole method. It’s not simple cut-and-paste – molecules need to be designed, then tested in cells; then delivery method needs to be again tested, but this time in animal models. It will be especially daunting in his case, as this is disorder of skin cells. We are nearly “illiterate” in terms of editing skin cells.

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