Constricted migration modulates stem cell differentiation

Tissue regeneration at an injured site depends on proliferation, migration, and differentiation of resident stem or progenitor cells, but solid tissues are often sufficiently dense and constricting that nuclei are highly stressed by migration. In this study, constricted migration of myoblastic cell types and mesenchymal stem cells (MSCs) increases nuclear rupture, increases DNA damage, and modulates differentiation. Fewer myoblasts fuse into regenerating muscle in vivo after constricted migration in vitro, and myodifferentiation in vitro is likewise suppressed. Myosin II inhibition rescues rupture and DNA damage, implicating nuclear forces, while mitosis and the cell cycle are suppressed by constricted migration, consistent with a checkpoint. Although perturbed proliferation fails to explain defective differentiation, nuclear rupture mislocalizes differentiation-relevant MyoD and KU80 (a DNA repair factor), with nuclear entry of the DNA-binding factor cGAS. Human MSCs exhibit similar damage, but osteogenesis increases—which is relevant to bone and to calcified fibrotic tissues, including diseased muscle. Tissue repair can thus be modulated up or down by the curvature of pores through which stem cells squeeze.

[1]  Lucas R. Smith,et al.  Rescue of DNA damage after constricted migration reveals a mechano-regulated threshold for cell cycle , 2019, The Journal of cell biology.

[2]  D. Fox,et al.  Muscle Stem Cells Give Rise to Rhabdomyosarcomas in a Severe Mouse Model of Duchenne Muscular Dystrophy. , 2019, Cell reports.

[3]  R. Greenberg,et al.  Rescue of DNA damage in cells after constricted migration reveals bimodal mechano-regulation of cell cycle , 2018 .

[4]  M. Mahdy.  Skeletal muscle fibrosis: an overview , 2018, Cell and Tissue Research.

[5]  Lucas R. Smith,et al.  Nuclear rupture at sites of high curvature compromises retention of DNA repair factors , 2018, The Journal of cell biology.

[6]  R. Greenberg,et al.  Constricted migration increases DNA damage and independently represses cell cycle , 2018, Molecular biology of the cell.

[7]  Jiyeon Kim,et al.  Vitamin C-linker-conjugated tripeptide AHK stimulates BMP-2-induced osteogenic differentiation of mouse myoblast C2C12 cells. , 2018, Differentiation; research in biological diversity.

[8]  Lucas R. Smith,et al.  Regulation of fibrosis in muscular dystrophy. , 2018, Matrix biology : journal of the International Society for Matrix Biology.

[9]  Dennis E Discher,et al.  Mitotic progression following DNA damage enables pattern recognition within micronuclei , 2017, Nature.

[10]  J. Parvin,et al.  Differential requirements for DNA repair proteins in immortalized cell lines using alternative lengthening of telomere mechanisms , 2017, Genes, chromosomes & cancer.

[11]  M. Djuric,et al.  Porotic paradox: distribution of cortical bone pore sizes at nano- and micro-levels in healthy vs. fragile human bone , 2017, Journal of Materials Science: Materials in Medicine.

[12]  Andrea J. Liu,et al.  DNA Damage Follows Repair Factor Depletion and Portends Genome Variation in Cancer Cells after Pore Migration , 2017, Current Biology.

[13]  M. Hetzer,et al.  Nuclear envelope rupture is induced by actin-based nucleus confinement , 2016, The Journal of cell biology.

[14]  Dingbiao Long,et al.  MicroRNA-199a Targets the Fatty Acid Transport Protein 1 Gene and Inhibits the Adipogenic Trans-Differentiation of C2C12 Myoblasts , 2016, Cellular Physiology and Biochemistry.

[15]  Sandra J Shefelbine,et al.  Bone mechanical properties and changes with osteoporosis. , 2016, Injury.

[16]  E. Bernotiene,et al.  Scaffolds and cells for tissue regeneration: different scaffold pore sizes—different cell effects , 2016, Cytotechnology.

[17]  Jan Lammerding,et al.  Nuclear envelope rupture and repair during cancer cell migration , 2016, Science.

[18]  R. Voituriez,et al.  ESCRT III repairs nuclear envelope ruptures during cell migration to limit DNA damage and cell death , 2016, Science.

[19]  Lucas R. Smith,et al.  Increased collagen cross‐linking is a signature of dystrophin‐deficient muscle , 2016, Muscle & nerve.

[20]  J. Lippincott-Schwartz,et al.  Intravital Imaging Reveals Ghost Fibers as Architectural Units Guiding Myogenic Progenitors during Regeneration. , 2016, Cell stem cell.

[21]  K. Gundersen.  Muscle memory and a new cellular model for muscle atrophy and hypertrophy , 2016, Journal of Experimental Biology.

[22]  J. Lammerding,et al.  Non-muscle myosin IIB is critical for nuclear translocation during 3D invasion , 2015, The Journal of cell biology.

[23]  Sangkyun Cho,et al.  Fractal heterogeneity in minimal matrix models of scars modulates stiff-niche stem-cell responses via the nuclear exit of a mechanorepressor , 2015, Nature materials.

[24]  F. Muntoni,et al.  The effect of the muscle environment on the regenerative capacity of human skeletal muscle stem cells , 2015, Skeletal Muscle.

[25]  Bing Wang,et al.  Activation of non-myogenic mesenchymal stem cells during the disease progression in dystrophic dystrophin/utrophin knockout mice. , 2015, Human molecular genetics.

[26]  J. Morgan,et al.  Satellite cells from dystrophic muscle retain regenerative capacity , 2015, Stem cell research.

[27]  Lucas R. Smith,et al.  SMASH – semi-automatic muscle analysis using segmentation of histology: a MATLAB application , 2014, Skeletal Muscle.

[28]  V. Mouly,et al.  MMP-14 is necessary but not sufficient for invasion of three-dimensional collagen by human muscle satellite cells. , 2014, American journal of physiology. Cell physiology.

[29]  Lucas R. Smith,et al.  Collagen content does not alter the passive mechanical properties of fibrotic skeletal muscle in mdx mice. , 2014, American journal of physiology. Cell physiology.

[30]  Richard T. Lee,et al.  Restoring Systemic GDF11 Levels Reverses Age-Related Dysfunction in Mouse Skeletal Muscle , 2014, Science.

[31]  Y. Asakura,et al.  Isolation, culture, and transplantation of muscle satellite cells. , 2014, Journal of visualized experiments : JoVE.

[32]  J. Irianto,et al.  Nuclear lamin stiffness is a barrier to 3D migration, but softness can limit survival , 2014, The Journal of cell biology.

[33]  David Hsu,et al.  OpenComet: An automated tool for comet assay image analysis , 2014, Redox biology.

[34]  E. Monti,et al.  Muscular dystrophies share pathogenetic mechanisms with muscle sarcomas. , 2013, Trends in molecular medicine.

[35]  Dennis E. Discher,et al.  Nuclear Lamin-A Scales with Tissue Stiffness and Enhances Matrix-Directed Differentiation , 2013, Science.

[36]  R. Lieber,et al.  Cellular mechanisms of tissue fibrosis. 4. Structural and functional consequences of skeletal muscle fibrosis. , 2013, American journal of physiology. Cell physiology.

[37]  J. Dutta,et al.  Inhibition of CK2 binding to BMPRIa induces C2C12 differentiation into osteoblasts and adipocytes , 2013, Journal of Cell Communication and Signaling.

[38]  F. Barr,et al.  Human Rhabdomyosarcoma Cell Lines for Rhabdomyosarcoma Research: Utility and Pitfalls , 2013, Front. Oncol..

[39]  Kenneth M. Yamada,et al.  At the leading edge of three-dimensional cell migration , 2012, Journal of Cell Science.

[40]  Z. Zeng,et al.  APLF promotes the assembly and activity of non‐homologous end joining protein complexes , 2012, The EMBO journal.

[41]  D. Discher,et al.  Crawling from soft to stiff matrix polarizes the cytoskeleton and phosphoregulates myosin-II heavy chain , 2012, The Journal of cell biology.

[42]  C. Hourde,et al.  Loss of a single allele for Ku80 leads to progenitor dysfunction and accelerated aging in skeletal muscle , 2012, EMBO molecular medicine.

[43]  P. Friedl,et al.  Intravital third harmonic generation microscopy of collective melanoma cell invasion , 2012, Intravital.

[44]  Johannes E. Schindelin,et al.  Fiji: an open-source platform for biological-image analysis , 2012, Nature Methods.

[45]  F. Muntoni,et al.  Donor Satellite Cell Engraftment is Significantly Augmented When the Host Niche is Preserved and Endogenous Satellite Cells are Incapacitated , 2012, Stem cells.

[46]  W. D. De Vos,et al.  Repetitive disruptions of the nuclear envelope invoke temporary loss of cellular compartmentalization in laminopathies. , 2011, Human molecular genetics.

[47]  C. Pirker,et al.  DNA Damage, Somatic Aneuploidy, and Malignant Sarcoma Susceptibility in Muscular Dystrophies , 2011, PLoS genetics.

[48]  F. Dilworth,et al.  Caspase 3/caspase-activated DNase promote cell differentiation by inducing DNA strand breaks , 2010, Proceedings of the National Academy of Sciences.

[49]  G. Davis,et al.  3D Timelapse Analysis of Muscle Satellite Cell Motility , 2009, Stem cells.

[50]  S. Sen,et al.  Matrix Elasticity Directs Stem Cell Lineage Specification , 2006, Cell.

[51]  G. Messina,et al.  p27Kip1 acts downstream of N-cadherin-mediated cell adhesion to promote myogenesis beyond cell cycle regulation. , 2005, Molecular biology of the cell.

[52]  Adam J. Engler,et al.  Myotubes differentiate optimally on substrates with tissue-like stiffness , 2004, The Journal of cell biology.

[53]  Ling Lin,et al.  Highly Coordinated Gene Regulation in Mouse Skeletal Muscle Regeneration* 210 , 2003, The Journal of Biological Chemistry.

[54]  J. Zhu,et al.  A myogenic differentiation checkpoint activated by genotoxic stress , 2002, Nature Genetics.

[55]  Jyj Wang,et al.  DNA damage and apoptosis , 2001, Cell Death and Differentiation.

[56]  K. Iguchi,et al.  Phosphatidylserine induces apoptosis in adherent cells , 2001, Apoptosis.

[57]  S. Manolagas,et al.  Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. , 2000, Endocrine reviews.

[58]  M. Pittenger,et al.  Multilineage potential of adult human mesenchymal stem cells. , 1999, Science.

[59]  G Cossu,et al.  Muscle regeneration by bone marrow-derived myogenic progenitors. , 1998, Science.

[60]  S. Tapscott,et al.  Deficiency in rhabdomyosarcomas of a factor required for MyoD activity and myogenesis. , 1993, Science.

[61]  D. Watt,et al.  In situ localisation of single-stranded DNA breaks in nuclei of a subpopulation of cells within regenerating skeletal muscle of the dystrophic mdx mouse. , 1992, Journal of cell science.

[62]  J. Shrager,et al.  The mdx mouse diaphragm reproduces the degenerative changes of Duchenne muscular dystrophy , 1991, Nature.

[63]  L. Hartwell,et al.  Checkpoints: controls that ensure the order of cell cycle events. , 1989, Science.

[64]  F. Farzaneh,et al.  DNA strand breaks and ADP-ribosyl transferase activation during cell differentiation , 1982, Nature.

[65]  K. Ranganathan,et al.  Traumatic muscle fibrosis: From pathway to prevention , 2017, The journal of trauma and acute care surgery.

[66]  D. Garry,et al.  Cardiotoxin Induced Injury and Skeletal Muscle Regeneration. , 2016, Methods in molecular biology.

[67]  Feodor Price,et al.  Satellite cells and the muscle stem cell niche. , 2013, Physiological reviews.