Niche stiffness underlies the ageing of central nervous system progenitor cells
Open accessAbstract
Ageing causes a decline in tissue regeneration owing to a loss of function of adult stem cell and progenitor cell populations 1. 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)2. A relatively overlooked potential source of this loss of function is the stem cell 'niche'-a set of cell-extrinsic cues that include chemical and mechanical signals 3,4. Here we show that 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, we find that 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.
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Increased stiffness was observed in ageing brain tissue.
“Increased stiffness was observed in ageing brain tissue80.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [80]
ECM stiffness has a strong effect on OPC proliferation and differentiation during ageing; OPC niche stiffness drastically increases with age; a softer niche is sufficient to restore OPC proliferation; and niche stiffness is mediated by the mechanosensitive ion channel PIEZO1 in OPCs.
“In the central nervous system, transplantation experiments in rats indicate that ECM stiffness has a strong effect on OPC proliferation and differentiation during ageing80. OPC niche stiffness drastically increased with age, as determined by atomic force microscopy in the prefrontal cortex80. A softer niche is sufficient to restore OPC proliferation. Interestingly, niche stiffness is mediated by”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [80]
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Cites
Transcript-level expression analysis of RNA-seq experiments with HISAT, StringTie and Ballgown
Pertea, M., Kim, D., Pertea, G. M., Leek, J. T., & Salzberg, S. L. (2016) · Nature Protocols · doi:10.1038/nprot.2016.095 · Cited by 6,708 · see citing works
Ueber die Berührung fester elastischer Körper.
Hertz, H. (1882) · Journal für die reine und angewandte Mathematik (Crelles Journal) · doi:10.1515/crll.1882.92.156 · Cited by 4,798 · see citing works
On the Contact of Elastic Solids
Hertz (1882) · Journal für die reine und angewandte Mathematik (Crelles Journal) · Cited by 3,051 · see citing works
Nuclear Lamin-A Scales with Tissue Stiffness and Enhances Matrix-Directed Differentiation
Swift, J., Ivanovska, I. L., Buxboim, A., Harada, T., Dingal, P. C. D. P., Pinter, J., Pajerowski, J. D., Spinler, K. R., Shin, J., Tewari, M., et al. (2013) · Science · doi:10.1126/science.1240104 · Cited by 1,998 · see citing works
Chan, K. Y., Jang, M. J., Yoo, B. B., Greenbaum, A., Ravi, N., Wu, W.-L., Sánchez-Guardado, L., Lois, C., Mazmanian, S. K., Deverman, B. E., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4593 · Cited by 1,578 · see citing works
Piezo1 integration of vascular architecture with physiological force
Li, J., Hou, B., Tumova, S., Muraki, K., Bruns, A. F., Ludlow, M. J., Sedó, A., Hyman, A. J., McKeown, L., Young, R. S., et al. (2014) · Nature · doi:10.1038/nature13701 · Cited by 1,210 · see citing works
In vivo genome editing via CRISPR/Cas9 mediated homology-independent targeted integration
Suzuki, K., Tsunekawa, Y., Hernandez-Benitez, R., Wu, J., Zhu, J., Kim, E. J., Hatanaka, F., Yamamoto, M., Araoka, T., Li, Z., et al. (2016) · Nature · doi:10.1038/nature20565 · Cited by 1,150 · see citing works
Crowding induces live cell extrusion to maintain homeostatic cell numbers in epithelia
Eisenhoffer, G. T., Loftus, P. D., Yoshigi, M., Otsuna, H., Chien, C.-B., Morcos, P. A., & Rosenblatt, J. (2012) · Nature · doi:10.1038/nature10999 · Cited by 876 · see citing works
Altered human oligodendrocyte heterogeneity in multiple sclerosis
Jäkel, S., Agirre, E., Mendanha Falcão, A., van Bruggen, D., Lee, K. W., Knuesel, I., Malhotra, D., ffrench-Constant, C., Williams, A., & Castelo-Branco, G. (2019) · Nature · doi:10.1038/s41586-019-0903-2 · Cited by 854 · see citing works
Mechanosensing is critical for axon growth in the developing brain
Koser, D. E., Thompson, A. J., Foster, S. K., Dwivedy, A., Pillai, E. K., Sheridan, G. K., Svoboda, H., Viana, M., Costa, L. D. F., Guck, J., et al. (2016) · Nature Neuroscience · doi:10.1038/nn.4394 · Cited by 649 · see citing works
Self-citationSim, F. J., Zhao, C., Penderis, J., & Franklin, R. J. M. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-07-02451.2002 · Cited by 625 · see citing works
Self-citationNissim, L., Perli, S. D., Fridkin, A., Pérez‐Piñera, P., & Lu, T. K. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.04.022 · Cited by 430 · see citing works
Mechanical regulation of stem-cell differentiation by the stretch-activated Piezo channel
He, L., Si, G., Huang, J., Samuel, A. D. T., & Perrimon, N. (2018) · Nature · doi:10.1038/nature25744 · Cited by 348 · see citing works
Goodell, M. A., & Rando, T. A. (2015) · Science · doi:10.1126/science.aab3388 · Cited by 347 · see citing works
A robust system for production of minicircle DNA vectors
Kay, M. A., He, C.-Y., & Chen, Z.-Y. (2010) · Nature Biotechnology · doi:10.1038/nbt.1708 · Cited by 329 · see citing works
Stem Cell Review Series: Aging of the skeletal muscle stem cell niche
Gopinath, S. D., & Rando, T. A. (2008) · Aging Cell · doi:10.1111/j.1474-9726.2008.00399.x · Cited by 262 · see citing works
Christ, A. F., Franze, K., Gautier, H. O. B., Moshayedi, P., Fawcett, J. W., Franklin, R. J. M., Káradóttir, R. T., & Guck, J. R. (2010) · Journal of Biomechanics · doi:10.1016/j.jbiomech.2010.07.002 · Cited by 243 · see citing works
Self-citationAtlas of the Postnatal Rat Brain in Stereotaxic Coordinates
Khazipov, R., Zaynutdinova, D., Ogievetsky, E., Valeeva, G. R., Mitrukhina, O., Manent, J., & Represa, A. (2015) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2015.00161 · Cited by 240 · see citing works
Lack of Replicative Senescence in Cultured Rat Oligodendrocyte Precursor Cells
Tang, D. G., Tokumoto, Y. M., Apperly, J. A., Lloyd, A. C., & RAFF, M. C. (2001) · Science · doi:10.1126/science.1056780 · Cited by 228 · see citing works
Extensive remyelination of the CNS leads to functional recovery
Duncan, I. D., Brower, A., Kondo, Y., Curlee, J. F., & Schultz, R. D. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0812500106 · Cited by 227 · see citing works
Integrin activation by Fam38A uses a novel mechanism of R-Ras targeting to the endoplasmic reticulum
McHugh, B. J., Buttery, R. C., Lad, Y., Banks, S., Haslett, C., & Sethi, T. (2009) · Journal of Cell Science · doi:10.1242/jcs.056424 · Cited by 217 · see citing works
Keough, M. B., Rogers, J. A., Zhang, P., Jensen, S. K., Stephenson, E. L., Chen, T., Hurlbert, M. G., Lau, L. W., Rawji, K. S., Plemel, J. R., et al. (2016) · Nature Communications · doi:10.1038/ncomms11312 · Cited by 212 · see citing works
Remyelination of mouse spinal cord axons demyelinated by local injection of lysolecithin
Jeffery, N. D., & Blakemore, W. F. (1995) · Journal of Neurocytology · doi:10.1007/bf01191213 · Cited by 185 · see citing works
CNS Cell Distribution and Axon Orientation Determine Local Spinal Cord Mechanical Properties
Koser, D. E., Moeendarbary, E., Hanne, J., Küerten, S., & Franze, K. (2015) · Biophysical Journal · doi:10.1016/j.bpj.2015.03.039 · Cited by 179 · see citing works
Self-citationMcHugh, B. J., Murdoch, A., Haslett, C., & Sethi, T. (2012) · PLoS ONE · doi:10.1371/journal.pone.0040346 · Cited by 169 · see citing works
Delayed Changes in Growth Factor Gene Expression during Slow Remyelination in the CNS of Aged Rats
Hinks, G. L., & Franklin, R. J. M. (2000) · Molecular and Cellular Neuroscience · doi:10.1006/mcne.2000.0897 · Cited by 156 · see citing works
Self-citationMoshayedi, P., Costa, L. D. F., Christ, A., Lacour, S. P., Fawcett, J. W., Guck, J. R., & Franze, K. (2010) · Journal of Physics Condensed Matter · doi:10.1088/0953-8984/22/19/194114 · Cited by 148 · see citing works
Self-citationSellers, D. L., Maris, D. O., & Horner, P. J. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.4538-08.2009 · Cited by 130 · see citing works
Spatial mapping of the mechanical properties of the living retina using scanning force microscopy
Franze, K., Francke, M., Günter, K., Christ, A. F., Körber, N., Reichenbach, A., & Guck, J. R. (2011) · Soft Matter · doi:10.1039/c0sm01017k · Cited by 102 · see citing works
Self-citation3D culture of murine neural stem cells on decellularized mouse brain sections
Waele, J. D., Reekmans, K., Daans, J., Goossens, H., Berneman, Z. N., & Ponsaerts, P. (2014) · Biomaterials · doi:10.1016/j.biomaterials.2014.11.025 · Cited by 92 · see citing works
Boudou, T., Ohayon, J., Arntz, Y., et al. (2006) · Journal of Biomechanics · doi:10.1016/j.jbiomech.2005.04.026 · Cited by 91 · see citing works
Challis, R. C., Kumar, S. R., Chan, K. Y., Challis, C., Jang, M. J., Rajendran, P. S., Tompkins, J. D., Shivkumar, K., Deverman, B. E., & Gradinaru, V. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/246405 · Cited by 17 · see citing works
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López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2023) · Cell · doi:10.1016/j.cell.2022.11.001 · Cited by 6,549 · see citing works
Ageing and rejuvenation of tissue stem cells and their niches
Brunet, A., Goodell, M. A., & Rando, T. A. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-022-00510-w · Cited by 407 · see citing works
Tissue Stem Cells: Architects of Their Niches
Fuchs, E., & Blau, H. M. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2020.09.011 · Cited by 332 · see citing works
Graves, J. S., Krysko, K. M., Hua, L. H., Absinta, M., Franklin, R. J. M., & Segal, B. M. (2023) · The Lancet Neurology · doi:10.1016/s1474-4422(22)00184-3 · Cited by 260 · see citing works
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Navarro Negredo, P., Yeo, R. W., & Brunet, A. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2020.07.002 · Cited by 246 · see citing works
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Wlaschek, M., Maity, P., Makrantonaki, E., & Scharffetter-Kochanek, K. (2021) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2020.11.010 · Cited by 245 · see citing works
Koester, J., Miroshnikova, Y. A., Ghatak, S., Chacón-Martínez, C. A., Morgner, J., Li, X., Atanassov, I., Altmüller, J., Birk, D. E., Koch, M., et al. (2021) · Nature Cell Biology · doi:10.1038/s41556-021-00705-x · Cited by 117 · see citing works
Oligodendrocyte progenitor cells in Alzheimer's disease: from physiology to pathology
Zou, P., Wu, C., Liu, T. C.-Y., Duan, R., & Yang, L. (2023) · Translational Neurodegeneration · doi:10.1186/s40035-023-00385-7 · Cited by 97 · see citing works
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Nguyen, B., Bix, G., & Yao, Y. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00502-y · Cited by 75 · see citing works
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Gross, P. S., Durán-Laforet, V., Ho, L. T., Melchor, G. S., Zia, S., Manavi, Z., Barclay, W. E., Lee, S. H., Shults, N., Selva, S., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-57632-w · Cited by 62 · see citing works
“Other factors known to change with age include increased chronic in fl ammation 69 , modi fi ed niche stiffness 70 , and inef fi cient myelin debris removal and processing by microglia and macrophages 71 .”
Rivera, A. D., Pieropan, F., Chacon‐De‐La‐Rocha, I., Lecca, D., Abbracchio, M. P., Azim, K., & Butt, A. M. (2021) · Aging Cell · doi:10.1111/acel.13335 · Cited by 61 · see citing works
Marangon, D., Caporale, N., Boccazzi, M., Abbracchio, M. P., Testa, G., & Lecca, D. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.748849 · Cited by 34 · see citing works
CRISPR-edited human ES-derived oligodendrocyte progenitor cells improve remyelination in rodents
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Self-citation
- Authors
- Segel, M., Neumann, B., Hill, M. F. E., Weber, I. P., Viscomi, C., Zhao, C., Young, A., Agley, C. C., Thompson, A. J., Gonzalez, G. A., Sharma, A., Holmqvist, S., Rowitch, D. H., Franze, K., Franklin, R. J. M., & Chalut, K. J.
- Affiliations
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Cambridge (GB)
- Corresponding author
- Franklin, Robin J. M.
- Chalut, Kevin J.
- ORCID
- Venue
- Nature
- Published
- 2019-08-15
- Volume
- 573
- Issue
- 7772
- Pages
- 130-134
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7025879
- OpenAlex
- W2968420254
- Cited by
- 532
- References
- 33
- Citations by year
- 2026: 75 · 2025: 76 · 2024: 85 · 2023: 85 · 2022: 71 · 2021: 65 · 2020: 62 · 2019: 12
- FWCI
- 19.77
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-08-29)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- Apollo
- Funders
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Wellcome Trust (772426, 203151/Z/16/Z, 203151)
- Multiple Sclerosis Society
- Rosetrees Trust
- Cambridge University Hospitals (146281)
- Directorate for Biological Sciences
- Medical Research Council (MC_PC_12009, MR/M011089/1, MR/R015635/1, MR/K017047/1)
- Biotechnology and Biological Sciences Research Council (BB/N006402/1, BB/M008827/1)
- H2020 European Research Council (772798, 772426)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- tissue stiffness, aging, oligodendrocyte precursor cells, stem cell niche, mechanical signalling, Piezo1, mechanosensitive ion channels, stem cell rejuvenation, synthetic scaffolds, cell proliferation and differentiation, central nervous system development, tissue regeneration
- MeSH terms
- Aging, Animals, Animals, Newborn, Cell Count, Central Nervous System, Extracellular Matrix, Female, Humans, Ion Channels, Membrane Proteins, Oligodendroglia, Multipotent Stem Cells, Rats, Adult Stem Cells, Stem Cell Niche
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