The role of the immune microenvironment in bone, cartilage, and soft tissue regeneration: from mechanism to therapeutic opportunity

Abstract

Bone, cartilage, and soft tissue regeneration is a complex spatiotemporal process recruiting a variety of cell types, whose activity and interplay must be precisely mediated for effective healing post-injury. Although extensive strides have been made in the understanding of the immune microenvironment processes governing bone, cartilage, and soft tissue regeneration, effective clinical translation of these mechanisms remains a challenge. Regulation of the immune microenvironment is increasingly becoming a favorable target for bone, cartilage, and soft tissue regeneration; therefore, an in-depth understanding of the communication between immune cells and functional tissue cells would be valuable. Herein, we review the regulatory role of the immune microenvironment in the promotion and maintenance of stem cell states in the context of bone, cartilage, and soft tissue repair and regeneration. We discuss the roles of various immune cell subsets in bone, cartilage, and soft tissue repair and regeneration processes and introduce novel strategies, for example, biomaterial-targeting of immune cell activity, aimed at regulating healing. Understanding the mechanisms of the crosstalk between the immune microenvironment and regeneration pathways may shed light on new therapeutic opportunities for enhancing bone, cartilage, and soft tissue regeneration through regulation of the immune microenvironment.

Keywords: Biomaterials; Cell-cell interaction; Immune microenvironment; Regeneration; Tissue engineering.

Fig. 1

Important immune molecules and signaling during tissue regeneration. Four continuous and overlapping stages involved in tissue regeneration process, including hemostasis, inflammation, repair, and remodeling. These stages were tightly controlled and the development of these stages is dependent on the regulatory roles of immune cells, particularly at the inflammatory stage, thus determining the effectiveness of the subsequent repair and remodeling stages. MMPs matrix metalloproteinases, MSCs mesenchymal stem cells, NK natural killer, TGF-β transforming growth factor-β, TIMPs tissue inhibitor of metalloproteinases, CCL2 chemokine (C-C motif) ligand 2, MCP-1 monocyte chemoattractant protein-1, TNF-α tumor necrosis factor-α, IFN-γ interferon gamma, ILC1 unconventional NK cells, PGDF-BB platelet-derived growth factor BB

Fig. 2

The important roles of T cells in the regulation of tissue regeneration. a Tregs modulate the activity of many other types of stem and progenitor cells involved in regeneration, and have become a crucial cell type for tissue repair and regeneration. b γδ T cells promote tissue repair and regeneration through communication with tissue stem cells. c CD4 T cells enhance tissue regeneration through the regulation of macrophages and fibroblasts, and CD8 T cells impair bone remodeling by hindering MSC proliferation and differentiation. MSCs mesenchymal stem cells

Fig. 3

Biomaterial chemistry-based immunomodulation for cartilage regeneration. a Proteomic evaluation of decellularized cartilage ECM [266]. b Preparation of Col/PDA/HA hydrogel scaffold and therapeutic mechanism for cartilage regeneration [268]. Col collagen, ECM extracellular matrix, HA hyaluronic acid, PDA polydopamine, PEGDE polyethylene (glycol) Diacrylate, BMSCs bone marrow mesenchymal stem cells

Fig. 4

Biomaterial-based delivery system and physical property-based immunomodulation for cartilage regeneration. a Schematic representation of an IL-4-loaded bi-layer 3D printed scaffold for osteochondral regeneration [273]. b Schematic illustration of a cartilage ECM scaffold combined with Wharton’s jelly mesenchymal stem cell-derived sEVs for osteochondral regeneration [278]. c Effects of PCL/EUG scaffolds with different stiffness (akin to normal/osteoarthritic cartilage) on macrophage secretion behavior, adapted with permission from ref. [280], Elsevier. ECM extracellular matrix, EUG Eucommia ulmoides gum, PCL polycaprolactone, M1CM m1 macrophage conditional medium, DLP digital light projector, HA hyaluronic acids, FDM fused deposition modeling, ACECM acellular cartilage extracellular matrix

Fig. 5

Biomaterial-based immunomodulation for soft tissue regeneration. a Schematic illustration of ADSCs-seeded chitosan/difunctional polyurethane hydrogel for the treatment of chronic diabetic skin wounds, adapted with permission from ref. [289]. b The hybrid hydrogel loaded with miR-223-laden nanoparticles promotes wound healing through increased M2 macrophage polarization, adapted with permission from ref. [290], Wiley online library. c Pseudotime analysis of the FTY720-induced increase in immune cell infiltration into a muscle defect area 3 days post-VML injury [291]. Copyright 2018, Elsevier. d Preparation of PLA electrospun fibers combined with pH-responsive IL-4 plasmid-loaded liposomes for the treatment of acute spinal cord injury. Copyright 2020, Nature Publishing Group [292]. e Development of an electrospun UPy-PCL scaffold functionalized with IL-4 and heparin for vascular damage repair [293]. Copyright 2021, Wiley online library. ADSCs adipose tissue-derived mesenchymal stem cells, PCL polycaprolactone, PLA polylactic acid, UPy ureido-pyrimidinone, VML volumetric muscle loss