How Stiff is your brain?

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This study examines what in the brain influences the generation of early myelinating cells and they find that the stiffness of the tissue makes a difference. They find that a protein called PIEZO is important. This is called FAM38 in mice.

Data from Brainseq2

Lets hope that rodents translate to humans because the protein expression profile is different, is this because mice only last 2 years verses many more years for the humans

Niche stiffness underlies the ageing of central nervous system progenitor cells. Segel M, Neumann B, Hill MFE, Weber IP, Viscomi C, Zhao C, Young A, Agley CC, Thompson AJ, Gonzalez GA, Sharma A, Holmqvist S, Rowitch DH, Franze K, Franklin RJM, Chalut KJ. Nature. 2019 Aug 15. doi: 10.1038/s41586-019-1484-9. [Epub ahead of print]

Ageing causes a decline in tissue regeneration owing to a loss of function of adult stem cell and progenitor cell populations. One example is the deterioration of the regenerative capacity of the widespread and abundant population of central nervous system (CNS) multipotent stem cells known as oligodendrocyte progenitor cells (OPCs). A relatively overlooked potential source of this loss of function is the stem cell ‘niche’-a set of cues that include chemical and mechanical signals. The OPC microenvironment stiffens with age, and that this mechanical change is sufficient to cause age-related loss of function of OPCs. Using biological and synthetic scaffolds to mimic the stiffness of young brains, isolated aged OPCs cultured on these scaffolds are molecularly and functionally rejuvenated. When we disrupt mechanical signalling, the proliferation and differentiation rates of OPCs are increased. We identify the mechanoresponsive ion channel PIEZO1 as a key mediator of OPC mechanical signalling. Inhibiting PIEZO1 overrides mechanical signals in vivo and allows OPCs to maintain activity in the ageing CNS. We also show that PIEZO1 is important in regulating cell number during CNS development. Thus we show that tissue stiffness is a crucial regulator of ageing in OPCs, and provide insights into how the function of adult stem and progenitor cells changes with age. Our findings could be important not only for the development of regenerative therapies, but also for understanding the ageing process itself.

So the question is how do you make an old brain young, the Cambridge group may have the answer, but we will have to wait until theis reaches the shelves but they have been talking bout it for 2 years. This is more good stuff.

However, I do need to throw a scanner in the works abit. It is vital that the claiims that humans myelinate in a different t anway to rodents is addressed. The challenge has been made and at the moment the rodent myelinators are ingnoring or simply saying the former is not true. However, this challenge has come from more than one source and the data needs to be challenged properly. If not this is simply sexy science that is going nowhere

About the author

MouseDoctor

5 comments

  • Lolllll 🙂

    Eyestarday i was reading Glia 2019 abstract ( a conference you were in, july this year)

    T08-009A
    Epigenetic mechanisms underlying oligodendrocyte differentiation enhanced by mechanotransduction

    And they say the exact oposite 🙂 🙂

    “it was shown that brain softening occurs with physiological ageing”

    Oligodendrocytes (OLs) are mechanosensitive cells, since their differentiation, migration, survival and
    proliferation are influenced by mechanical cues. Our group demonstrated that rat brain-compliant substrates
    (6.5kPa) enhanced the differentiation of OLs in vitro and this effect was potentiated in presence of laminin-2, an
    extracellular protein that promotes OL differentiation. Recently, using the non-invasive technique magnetic
    resonance elastography, it was shown that brain softening occurs with physiological ageing. Strikingly,
    individuals with multiple sclerosis (MS) present exacerbated softening when compared with age- and gendermatched
    controls, presumably due to deregulated extracellular matrix, cell death and consequent loss of
    mechanostasis (mechanical homeostasis). Taken together, these evidences suggest that changes in mechanical
    properties of the brain might have an important impact on cellular processes of OLs (namely their differentiation),
    with specific relevance in the context of MS.
    The mechanotransduction mechanisms involved in OL differentiation have not yet been fully elucidated, but it
    was reported that mechanical forces induce changes in chromatin structure, namely through mechanisms
    dependent on histones methylation. Gene expression and cell fate are controlled by epigenetic mechanisms,
    which play a key role on OL biology. Hence, we are dissecting the mechanisms underlying the enhancement of
    OL differentiation by mechanotransduction focusing on epigenetic modifications, namely citrullination by peptidylarginine
    deiminase 2 (PADI2).
    We observed changes on epigenetic markers through mechanisms dependent on histones citrullination and
    PADI2 protein level in OLs differentiated on substrates with distinct degrees of stiffness, suggesting a novel
    chromatin regulation mechanism on OLs in response to mechanical cues. Multiple sclerosis patients present
    higher levels of PADI2 and enhanced enzyme activity in normal appearing white mater with higher citrullination
    of myelin basic protein (MBP) and histones, which indicates that our findings may be relevant for MS.

    glia 2019(Porto) abstracts pag 298

    Strange strange world

    Who´s right who`s wrong

  • “Inhibiting PIEZO1 overrides mechanical signals in vivo and allows OPCs to maintain activity in the ageing CNS.”

    How do the authors know that removing the brakes on oligodendrocyte will not cause an increase in malignant potential, especially in humans?

    Do you think, MD, that remyelination therapies hold more potential for neuroprotection than say current neuroprotective agents being studied, like Na channel blockers, statins, alpha lipoid acid etc? In other words, could the treatment pyramid be more simple with just neuroinflammation-remyelination-neurorestoration?

  • Answer?

    So i email both studies to comment on one another and the Piezo study reply 🙂

    Hi Luis,

    Thanks for your interest in the paper. I can’t comment on the work because I hadn’t seen it before and to my knowledge it hasn’t been published. The link you sent was for a poster abstract. They use magnetic resonance elastography, I gather, though I don’t know if it’s a global measurement of the CNS, and I don’t know if that is a good direct measure of tissue stiffness anyway. To be honest, from everything we know about continual extracellular matrix deposition in the brain throughout our lives, I’d be very surprised if the human brain gets softer as we age. At any rate, that’s definitely not what our data showed, but we will continue to monitor the literature for any work coming out from that group.

    Best wishes,

    Kevin

    • Answer part 2

      So the other study author reply 🙂

      Good morning Luis,

      My name is Tânia I am the first author of the study “Epigenetic mechanisms underlying oligodendrocyte differentiation enhanced by mechanotransduction” that I am developing under the guidance of Dr Mário Grãos (in cc) and Dr. Gonçalo Castelo-Branco (in cc). In our summary we indicate that there is a decrease in brain stiffness with aging and the development of neurodegenerative diseases based on the following studies:

      https://doi.org/10.1371/journal.pone.0023451

      https://doi.org/10.1371/journal.pone.0029888

      https://doi.org/10.1016/j.nicl.2015.12.007

      doi: 10.1002 / jmri.24977

      In all of these studies, a noninvasive technique was used to measure brain stiffness in vivo – magnetic resonance elastography (MRE). With this technique it is possible to estimate the average stiffness of the brain as well as of some specific regions in vivo without resorting to any type of surgery or invasive procedure.

      In the recent study, the degree of stiffness is measured using an invasive technique – atomic force microscopy (AFM). AFM is a technique that allows image acquisition and mechanical characterization with high resolution and sensitivity in the measurement of forces (in the order of piconewton). Using AFM we can obtain information on the degree of rigidity in microscale or nanoscale which allows to calculate the strength of cell-cell or extracellular matrix-cell interaction. However, it is not possible to have a degree of mass stiffness as achieved by MRE. In addition this technique is invasive and requires surgery because there has to be contact with the tissue. In the case of the most recent article, measurements were made on post mortem brain slices.

      In short, the results of the articles we cited and the results of this last article were obtained by different techniques that present very different approach methods, which may lead to different results.

      So far, I am not aware of any study comparing these two measurement methods. For our study we based on the results obtained by MRE because we consider that the MRE technique is non-invasive and has the advantage that it can be performed on living organisms without any impact on their integrity, while the AFM technique is performed on post tissues. Mortem

      I am available for any further clarification.

      Best regards,

By MouseDoctor

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