Designing synthetic materials to control stem cell phenotype

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The micro-environment in which stem cells reside regulates their fate, and synthetic materials have recently been designed to emulate these regulatory processes for various medical applications. Ligands inspired by the natural extracellular matrix, cell–cell contacts, and growth factors have been incorporated into synthetic materials with precisely engineered density and presentation. Furthermore, material architecture and mechanical properties are material design parameters that provide a context for receptor–ligand interactions and thereby contribute to fate determination of uncommitted stem cells. Although significant progress has been made in biomaterials development for cellular control, the design of more sophisticated and robust synthetic materials can address future challenges in achieving spatiotemporal control of cellular phenotype and in implementing histocompatible clinical therapies.

Introduction

Stem cells are defined by their capacities for self-renewal and differentiation into one or more cell lineages [1, 2]. Without tight regulation or control of these properties, any derivative cell population, will exhibit a range of heterogeneous phenotypes, yielding artifacts that may complicate the development of cell therapies and pharmaceuticals. Recent work demonstrates that biomaterials (i.e. matrices, scaffolds, culture substrates) can present key regulatory signals that combine with other environmental and genetic influences to create synthetic micro-environments that control stem cell fate (Box 1). It can be argued that many of the promising therapeutic applications of stem cells will require instructive materials that exert active control over stem cell phenotype. Such materials may be designed for stem cell expansion and differentiation ex vivo, tissue regeneration via implantation with stem cells, or implantation alone to direct endogenous stem cell behavior. This review will discuss fundamental material properties that will be required to control stem cell function for any of these applications (Box 2).

Section snippets

Natural versus synthetic materials

Natural niches direct stem cell behavior in vivo to orchestrate the processes of tissue development, homeostasis, and physiological remodeling as well as injury recovery throughout life [3]. Components of native stem cell niches [e.g. extracellular matrix (ECM) proteins such as collagen and laminin, as well as proteoglycans such as heparan sulfate] can be isolated and used to create micro-environments that direct stem cell behavior in vitro, typically in combination with a cocktail of exogenous

Synthetic micro-environment design parameters

Regardless of which class is utilized, materials must be processed and functionalized for specific therapeutic applications. In particular, material properties important for controlling stem cell behavior include ligand identity, presentation, and density, as well as material architecture and mechanical properties (Figure 1). Effectively engineering these design parameters will yield materials that create an architecture that resembles their native environment, have controlled mechanical

Conclusions and future directions

Stem cells respond with exquisite sensitivity to cell-extrinsic signals, many of which can be engineered into synthetic materials. Emerging work in this field indicates that five key design parameters influence stem cell behavior in a biomaterial: ligand identity, presentation, and density; material architecture; and material mechanical properties. Together, these material properties coordinate the interplay between intrinsic and extrinsic determinants of stem cell fate to produce a desired

References and recommended reading

Papers of particular interest, published within the two-year period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was supported by the National Institute of Health (AR43187 and NS048248), Berkeley Futures Grant, Graduate Research and Education in Adaptive Bio-technology (GREAT) Training Program, UC Systemwide Biotechnology Research and Education Program (2005-280, KS), UC Berkeley Graduate Fellowship (JFP), and the National Science Foundation (Graduate Fellowships to JFP and KS).

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