Bioinspired Materials for Controlling Stem Cell Fate

Abstract

Although researchers currently have limited ability to mimic the natural stem cell microenvironment, recent work at the interface of stem biology and biomaterials science has demonstrated that control over stem cell behavior with artificial microenvironments is quite advanced. Embryonic and adult stem cells are potentially useful platforms for tissue regeneration, cell-based therapeutics, and disease-in-a-dish models for drug screening. The major challenge in this field is to reliably control stem cell behavior outside the body. Common biological control schemes often ignore physicochemical parameters that materials scientists and engineers commonly manipulate, such as substrate topography and mechanical and rheological properties. However, with appropriate attention to these parameters, researchers have designed novel synthetic microenvironments to control stem cell behavior in rather unnatural ways. In this Account, we review synthetic microenvironments that aim to overcome the limitations of natural niches rather than to mimic them. A biomimetic stem cell control strategy is often limited by an incomplete understanding of the complex signaling pathways that drive stem cell behavior from early embryogenesis to late adulthood. The stem cell extracellular environment presents a miscellany of competing biological signals that keep the cell in a state of unstable equilibrium. Using synthetic polymers, researchers have designed synthetic microenvironments with an uncluttered array of cell signals, both specific and nonspecific, that are motivated by rather than modeled after biology. These have proven useful in maintaining cell potency, studying asymmetric cell division, and controlling cellular differentiation. We discuss recent research that highlights important biomaterials properties for controlling stem cell behavior, as well as advanced processes for selecting those materials, such as combinatorial and high-throughput screening. Much of this work has utilized micro- and nanoscale fabrication tools for controlling material properties and generating diversity in both two and three dimensions. Because of their ease of synthesis and similarity to biological soft matter, hydrogels have become a biomaterial of choice for generating 3D microenvironments. In presenting these efforts within the framework of synthetic biology, we anticipate that future researchers may exploit synthetic polymers to create microenvironments that control stem cell behavior in clinically relevant ways.

The past, present and future in scaffold-based tendon treatments

“…However, direct cell injections have failed to deliver in a consistent manner in humans due to poor cell localisation [218][219][220][221], triggering an extensive investigation into the optimal cell carrier for tendon repair [1]. The ideal carrier system should prevent cell membrane rupture during the injection process; create increased tissue integration through fast in situ self-assembly; facilitate long-term cell survival and functionality maintenance; and allow spatiotemporal release of the cargo [222][223][224][225][226][227][228][229][230][231]. Preclinical data using either collagen [232] or fibrin [233] hydrogels have demonstrated improved mechanical properties, histological scores, tissue integration and restored functionality using TCs and various stem cell populations [234,235], however clinical use of injectable cell/hydrogel systems is still to be realised.…”

Synthesis and Characterization of Tunable Poly(Ethylene Glycol): Gelatin Methacrylate Composite Hydrogels

“…6,[11][12][13] Interestingly, both cell fate and cell function can be influenced by the hydrogel microenvironment. [14][15][16] Thus, ideally the hydrogel microenvironment should mimic the mechanical and biological demands and requirements of the tissues being replicated. 17 In the present study we have developed a photocrosslinkable composite hydrogel made from poly(ethylene glycol) dimethacrylate (PEGDMA MW 1000 Da) and methacrylated gelatin (GelMA).…”

Substrate topography: A valuable in vitro tool, but a clinical red herring for in vivo tenogenesis

“…electrospun polymeric fibres, extruded collagen fibres and isoelectrically focused collagen fibres) have been shown to maintain tenocyte phenotype and to differentiate stem cells towards tenogenic lineage in vitro and to induce acceptable regeneration in preclinical models, none of these technologies offers precise control over the spatial distribution of the fibres. Imprinting technologies, on the other hand, have demonstrated a diverse effect on a range of permanently differentiated and stem cell functions, including adhesion, orientation, secretome expression and lineage commitment [41][42][43][44][45][46][47][48] and offer significantly greater control over feature dimension and spacing. Specifically to tendon repair, such technologies have been shown to maintain tenocyte phenotype [38]; to promote aligned tendon-specific ECM deposition [39]; and to differentiate stem cells towards tenogenic lineage [40].…”