Developing a pro-regenerative biomaterial scaffold microenvironment requires T helper 2 cells

Abstract

Immune-mediated tissue regeneration driven by a biomaterial scaffold is emerging as an innovative regenerative strategy to repair damaged tissues. We investigated how biomaterial scaffolds shape the immune microenvironment in traumatic muscle wounds to improve tissue regeneration. The scaffolds induced a pro-regenerative response, characterized by an mTOR/Rictor-dependent T helper 2 pathway that guides interleukin-4–dependent macrophage polarization, which is critical for functional muscle recovery. Manipulating the adaptive immune system using biomaterials engineering may support the development of therapies that promote both systemic and local pro-regenerative immune responses, ultimately stimulating tissue repair.

Restoring Mucosal Barrier Function and Modifying Macrophage Phenotype with an Extracellular Matrix Hydrogel: Potential Therapy for Ulcerative Colitis

“…Although the signaling molecules that influence macrophage and lymphocyte phenotype transition are not fully understood, there is suggestive evidence that at least some of these regulators reside within the ECM [9,10,25]. Results of the present study suggest that ECMH modulates the innate immune response not by directly promoting an M2-like macrophage phenotype but rather by reducing the number of TNF expressing M1-like proinflammatory macrophages, thus shifting the microenvironmental milieu from inflammation to repair.…”

“…Regulatory M2-like macrophages have been associated with mucosal healing outcomes [21,22] in preclinical models of IBD. Similarly, the restoration of functional tissues via ECM bioscaffold mediated events in a variety of regenerative medicine applications has been shown to be either associated with, or dependent upon a timely shift in macrophage phenotype toward M2 predominance [23,24,25].…”

“…Recognition that effector cells of the immune system, such as the macrophages and Thelper cells, not only promote classic inflammatory processes but also orchestrate the temporal inhibition of inflammation and initiation of functional tissue remodeling [25,31,42,43,44,45] provides the opportunity to re-examine immunosuppressive strategies for treatment of diseases such as UC. Although the signaling molecules that influence macrophage and lymphocyte phenotype transition are not fully understood, there is suggestive evidence that at least some of these regulators reside within the ECM [9,10,25].…”

Pro‐Regenerative Hydrogel Restores Scarless Skin during Cutaneous Wound Healing

“…[34] Given the potential of immune modulating scaffolds for wound healing, we then nail down those hydrogels that can support M2 macrophages. Unlike typical methods of validating scaffolds in vivo followed by characterizing the macrophage phenotype via histology, [41] we proactively examined the impact of macromers on macrophage phenotype in vitro, thus determining the pro-regenerative scaffolds. Our studies indicated that DexIEME hydrogel produced less M1 proinflammatory response than Dex-AE, HA, and MatriStem, while it supported favorable M2 macrophage phenotype.…”

“…Sadtler et al recently reported that a collagen-based scaffold that was unable to induce M2 phenotype only led to incomplete tissue regeneration. [41] Surprisingly, DexIEME did not induce prominent M1 proliferation but favored higher M2 production, which is an ideal condition for tissue engineering and regenerative medicine. It is worth to note that hyaluronic acid (HA), often used for wound healing and attenuating scar formation, [28] also supported the M2 phenotype.…”