Matrix mechanics and stem cell differentiation: pathways into the Nucleus
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1
University of Pennsylvania, United States
Soft tissues such as fat bear little physical stress, whereas stiffer tissues like muscle and bone sustain high stress. We have begun to uncover systematic relationships between such tissue properties and differentiation processes, having first shown that a soft matrix helps specify soft tissue lineages while a stiff matrix helps specify stiff tissue lineages[1]. Proteomics analyses of embryonic and mature tissues[2] have now revealed that while collagens directly determine tissue elasticity E the nucleoskeletal protein lamin-A follows polymer physics-type scaling versus E. Lamin-A has been reported for decades to vary widely between tissues, and mutations in lamin-A cause diseases of multiple stiff tissues as well as accelerated aging syndromes with defects in stiff tissue repair. Differentiation of various stem cell types is generally modulated by lamin-A levels downstream of matrix E and soluble factors such as retinoids[2],[3], and we have uncovered multiple pathways that are co-regulated by lamin-A. Complementary insights are obtained from analyses in stem cells of the contractile cytoskeleton which not only physically stresses the nucleus but often contributes to key polarized processes of stem cells[4]. Matrices and forces - in 2D and 3D[5] and regardless of scarlike heterogeneity[6] - thus combine with soluble factors[7] to control lineages, lamins, and fates.
NIH-NCI U54 Physical Sciences in Oncology Centers, PSOC@Penn
References:
[1] A. Engler ... D.E. Discher. Matrix elasticity directs stem cell lineage specification. Cell 126: 677-689 (2006).
[2] J. Swift ... D.E. Discher. Nuclear Lamin-A Scales with Tissue Stiffness and Enhances Matrix-directed Differentiation. Science 341: 1240104-1 to 15 (2013).
[3] J-W. Shin ... D.E. Discher. Lamins regulate cell trafficking and lineage maturation of adult human hematopoietic cells. PNAS 110: 18892–18897 (2013).
[4] J-W. Shin ... D.E. Discher. Contractile forces sustain and polarize hematopoiesis from stem and progenitor cells. Cell Stem Cell 14: 81-93 (2014).
[5] F.Rehfeldt ... D.E. Discher. Hyaluronic Acid Matrices of Tunable Elasticity in 2D and 3D show Matrix Stiffness Dictates Cytoskeletal Order and Myosin-II phosphorylation within Stem Cells. Integrative Biology 4: 422-30 (2012).
[6] P.C.D.P. Dingal ... D.E. Discher. Fractal heterogeneity in minimal matrix models of scars modulates stiff-niche stem-cell responses via nuclear exit of a mechanorepressor. Nature Materials 14: 951–960 (2015).
[7] D.E. Discher, D.M. Mooney, P. Zandstra. Growth factors, matrices, and forces combine and control stem cells. Science 324: 1673-1677 (2009).
Keywords:
Hydrogel,
stem cell,
3D scaffold,
matrix-cell interaction
Conference:
10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016.
Presentation Type:
New Frontier Oral
Topic:
Biomaterials for mechanical interfaces
Citation:
Discher
DE
(2016). Matrix mechanics and stem cell differentiation: pathways into the Nucleus.
Front. Bioeng. Biotechnol.
Conference Abstract:
10th World Biomaterials Congress.
doi: 10.3389/conf.FBIOE.2016.01.01971
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Received:
27 Mar 2016;
Published Online:
30 Mar 2016.