Designing the stem cell microenvironment for guided connective tissue regeneration

Abstract

Adult mesenchymal stem cells (MSCs) are an attractive cell source for regenerative medicine because of their ability to self-renew and their capacity for multilineage differentiation and tissue regeneration. For connective tissues, such as ligaments or tendons, MSCs are vital to the modulation of the inflammatory response following acute injury while also interacting with resident fibroblasts to promote cell proliferation and matrix synthesis. To date, MSC injection for connective tissue repair has yielded mixed results in vivo, likely due to a lack of appropriate environmental cues to effectively control MSC response and promote tissue healing instead of scar formation. In healthy tissues, stem cells reside within a complex microenvironment comprising cellular, structural, and signaling cues that collectively maintain stemness and modulate tissue homeostasis. Changes to the microenvironment following injury regulate stem cell differentiation, trophic signaling, and tissue healing. Here, we focus on models of the stem cell microenvironment that are used to elucidate the mechanisms of stem cell regulation and inspire functional approaches to tissue regeneration. Recent studies in this frontier area are highlighted, focusing on how microenvironmental cues modulate MSC response following connective tissue injury and, more importantly, how this unique cell environment can be programmed for stem cell-guided tissue regeneration.

Bifunctional Nanoparticle‐Stabilized Hydrogel Colloidosomes Serve as both Extracellular Matrix and Bioactive Factor Delivery Vehicles

“…Establishment of a 3D microenvironment for cell differentiation is a key to the regeneration of various tissues. [ 1 ] To mimic natural microenvironments, a 3D construct should promote both strong cell–extracellular matrix (ECM) and cell–cell interactions [ 2 ] so that resident cells are supported for proliferation and functionalization. However, it is challenging to simultaneously enhance cell–ECM and cell–cell interactions in some tissue engineering strategies.…”

Biomaterials to Mimic and Heal Connective Tissues

“…TSPCs may play important roles in tendon homeostasis and healing capacity following injury, due both to their ability to differentiate into tenocytes and participate in paracrine signaling. [87,199] TSPCs are positive for stem cell markers (e.g., CD44, 90, and 146) [87,200] and negative for markers of other cell populations (e.g., endothelial cells, leukocytes, CD34, 45). [87] Several transcription factors (e.g., Scleraxis, Mohawk, Tenomodulin) and ECM proteins (collagen I, and members of the SLRP family) may be particularly important to evaluate as are expressed in naïve tendon.…”

“…[458] Augmentation of injured tendon with tendon derived cells, tendon stem/progenitor cells, and other stem cells (ASCs, MSCs, bmMSCs, iPSCs) may therefore offer therapeutic approaches to augment diseased tendon. [199] Additionally, much work has incorporated lessons learned from in vitro culture experiments that have emphasized how substrate mechanics, mechanical stimulation, media conditions, and growth factor supplementation can affect tendon cell behavior. Together, these approaches offer exciting avenues to improve tendon healing at the expense of increased complexity and regulation, discussed in Section 4.…”

Hydrogel screening approaches for bone and cartilage tissue regeneration

“…In vivo , SC behavior is guided by interactions with neighboring cells and dynamic signals presented by their residing ECM. The ECM provides resident SCs with structural support and a complex milieu of biochemical and biomechanical signals that collectively regulate stemness, proliferation, and differentiation . These interactions are highly dynamic and changes to the ECM from prolonged use, aging, injury, or disease can have profound effects on SC growth and function.…”

“…Due to the various ECM signals that regulate SC lineage commitment (Fig. ), tools to identify the optimal content and concentration of cell−cell and cell−ECM signals for osteogenic and chondrogenic differentiation would result in a more robust class of biomaterials for bone and cartilage tissue regeneration.…”