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Biophysics and dynamics of natural and engineered stem cell microenvironments

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Abstract Stem cells are defined by their ability to self‐renew and to differentiate into one or more mature lineages, and they reside within natural niches in many types of adult and embryonic tissues that present them with complex signals to regulate these two hallmark properties. The diverse nature of these in vivo microenvironments raises important questions about the microenvironmental cues regulating stem cell plasticity, and the stem cell field has built a strong foundation of knowledge on the biochemical identities and regulatory effects of the soluble, cellular, and extracellular matrix factors surrounding stem cells through the isolation and culture of stem cells in vitro within microenvironments that, in effect, emulate the properties of the natural niche. Recent work, however, has expanded the field's perspective to include biophysical and dynamic characteristics of the microenvironment. These include biomechanical characteristics such as elastic modulus, shear force, and cyclic strain; architectural properties such as geometry, topography, and dimensionality; and dynamic structures and ligand profiles. We will review how these microenvironmental characteristics have been shown to regulate stem cell fate and discuss future research directions that may help expand our current understanding of stem cell biology and aid its application to regenerative medicine. Copyright © 2009 John Wiley & Sons, Inc. This article is categorized under: Developmental Biology > Stem Cell Biology and Regeneration

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Biophysical and dynamic characteristics of natural and engineered microenvironments regulate stem cell fate. Biomechanical characteristics such as shear, strain, and stiffness are found in diverse natural microenvironments including the heart, bone, and brain and can be recapitulated in engineered systems. In addition, unique pinwheel architectures exist in NSC niches in the ventricular zone of the brain while cellular geometry controls MSC differentiation into adipocytes and osteoblasts on small and large adhesive islands. Engineered microenvironments can also be designed with topographical and dimensional cues. Lastly, dynamic presentation of mitogens and morphogens or degradation of ECM can regulate stem cell behavior. For example, oscillations in NSC expression of neurogenic factors like Dll1 (Delta‐like 1, a Notch ligand) maintain stem cell plasticity. ((a) Reprinted with permission from Ref 121. Copyright 2004 Elsevier. (b) Reprinted with permission from Ref 118. Copyright 2008 Elsevier. (c) Reprinted with permission from Ref 153. Copyright 2008 Elsevier).

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The hierarchy of microenvironmental cues and molecular transduction mechanisms regulating stem cell fate. Mechanical, architectural, dynamic, and biochemical properties define both engineered and natural microenvironments. A combination of molecular mechanisms such as biochemical signaling, gene expression, morphology, protein localization, and intracellular transport transduce these microenvironmental cues into stem cell fate choices. Microenvironmental cues may maintain stem cell homeostasis, induce differentiation, support self‐renewal, or regulate assembly.

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Elastic modulus variation within a single tissue. The hippocampus of rat brain exhibits heterogeneous elastic modulus ranging from ∼100 to ∼300 Pa (0% and 200% on the normalized color intensity scale bar, respectively). Stem cells exist in the subgranular zone of the dentate gyrus, a region of the hippocampus, and experience a specific microenvironmental stiffness. Scale bar is 1 mm. Reprinted from Elkin BS, Azeloglu EU, Costa KD, Morrison B. Mechanical heterogeneity of the rat hippocampus measured by atomic force microscope indentation. (Reprinted with permission. Copyright 2007 Mary Ann Liebert, Inc. Publishers).

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