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Outcomes following human dense connective tissue (DCT) repair are often variable and suboptimal, resulting in compromised function and development of chronic painful degenerative diseases. Moreover, biomarkers and mechanisms that guide good clinical outcomes after DCT injuries are mostly unknown. Here, we characterize the proteomic landscape of DCT repair following human Achilles tendon rupture and its association with long-term patient-reported outcomes. Moreover, the potential regulatory mechanisms of relevant biomarkers were assessed partly by gene silencing experiments. A mass-spectrometry based proteomic approach quantified a large number (769) of proteins, including 51 differentially expressed proteins among 20 good versus 20 poor outcome patients. A novel biomarker, elongation factor-2 (eEF2) was identified as being strongly prognostic of the 1-year clinical outcome. Further bioinformatic and experimental investigation revealed that eEF2 positively regulated autophagy, cell proliferation and migration, as well as reduced cell death and apoptosis, leading to improved DCT repair and outcomes. Findings of eEF2 as novel prognostic biomarker could pave the way for new targeted treatments to improve healing outcomes after DCT injuries. Trial registration : NCT02318472 registered 17 December 2014 and NCT01317160 registered 17 March 2011, with URL http://clinicaltrials.gov/ct2/show/NCT02318472 and http://clinicaltrials.gov/ct2/show/study/NCT01317160 .

Mapping a new therapeutic route can be fraught with challenges, but recent developments in the preparation and properties of small particles combined with significant improvements to tried and tested techniques offer refined cell targeting with tremendous translational potential. Regenerating new cells through the use of compounds that regulate epigenetic pathways represents an attractive approach that is gaining increased attention for the treatment of several diseases including Type 1 Diabetes and cardiomyopathy. However, cells that have been regenerated using epigenetic agents will still encounter immunological barriers as well as limitations associated with their longevity and potency during transplantation. Strategies aimed at protecting these epigenetically regenerated cells from the host immune response include microencapsulation. Microencapsulation can provide new solutions for the treatment of many diseases. In particular, it offers an advantageous method of administering therapeutic materials and molecules that cannot be substituted by pharmacological substances. Promising clinical findings have shown the potential beneficial use of microencapsulation for islet transplantation as well as for cardiac, hepatic, and neuronal repair. For the treatment of diseases such as type I diabetes that requires insulin release regulated by the patient's metabolic needs, microencapsulation may be the most effective therapeutic strategy. However, new materials need to be developed, so that transplanted encapsulated cells are able to survive for longer periods in the host. In this article, we discuss microencapsulation strategies and chart recent progress in nanomedicine that offers new potential for this area in the future.

Background To establish a strategy for stem cell-related tissue regeneration therapy, human gingival mesenchymal stem cells (hGMSCs) were loaded with three-dimensional (3D) bioengineered Matrigel matrix scaffolds in high-cell density microtissues to promote local tissue restoration. Methods The biological performance and stemness of hGMSCs under 3D culture conditions were investigated by viability and multidirectional differentiation analyses. A Sprague‒Dawley (SD) rat full-thickness buccal mucosa wound model was established, and hGMSCs/Matrigel were injected into the submucosa of the wound. Autologous stem cell proliferation and wound repair in local tissue were assessed by histomorphometry and immunohistochemical staining. Results Three-dimensional suspension culture can provide a more natural environment for extensions and contacts between hGMSCs, and the viability and adipogenic differentiation capacity of hGMSCs were significantly enhanced. An animal study showed that hGMSCs/Matrigel significantly accelerated soft tissue repair by promoting autologous stem cell proliferation and enhancing the generation of collagen fibers in local tissue. Conclusion Three-dimensional cell culture with hydrogel scaffolds, such as Matrigel, can effectively improve the biological function and maintain the stemness of stem cells. The therapeutic efficacy of hGMSCs/Matrigel was confirmed, as these cells could effectively stimulate soft tissue repair to promote the healing process by activating the host microenvironment and autologous stem cells. Graphical abstract

The transition from acute inflammation to chronic pain represents a significant clinical challenge, often driven by a failure of endogenous resolution programs. Specialized pro-resolving mediators (SPMs), derived from polyunsaturated fatty acids, are crucial for actively terminating inflammation and restoring tissue homeostasis. Maresin 1 (MaR1), a prototypical SPM biosynthesized from docosahexaenoic acid (DHA), has emerged as a powerful modulator of pain. This review comprehensively synthesizes the current preclinical evidence, primarily derived from preclinical animal models, detailing the analgesic effects of MaR1 across a spectrum of pain models, including inflammatory, neuropathic, postoperative, osteoarthritis-related pain, etc. We dissect the multifaceted mechanisms underlying its efficacy, which extend beyond simple anti-inflammation. MaR1 exerts its effects by: (1) attenuating neuroinflammation including the suppression of glial (microglia and astrocyte) activation and reprogramming macrophage phenotypes; (2) directly modulating neuronal function by inhibiting nociceptive ion channels (e.g. TRPV1) and reversing central synaptic plasticity; and (3) promoting robust tissue repair, including peripheral nerve regeneration. These actions are mediated through potential specific receptors, notably G-protein-coupled receptor 37-like 1 (GPR37L1) on glial cells and retinoic acid-related orphan receptor α (RORA) on neurons. While MaR1 demonstrates significant therapeutic potential, challenges related to its pharmacokinetic instability and observed sex-dependent analgesic effects must be addressed for successful clinical translation. This review provides a comprehensive mechanistic framework supporting MaR1 as a next-generation therapeutic candidate for pain management, and outlines the core research directions to overcome key translational barriers for MaR1-based therapies.

Tissue regeneration capabilities vary significantly throughout an organism’s lifespan. For example, mammals can fully regenerate until they reach specific developmental stages, after which they can only repair the tissue without restoring its original architecture and function. The high regenerative potential of fetal stages has been attributed to various factors, such as stem cells, the immune system, specific growth factors, and the presence of extracellular matrix molecules upon damage. To better understand the local differences between regenerative and reparative tissues, we conducted a comparative analysis of skin derived from mice at regenerative and reparative stages. Our findings show that both types of skin differ in their molecular composition, structure, and functionality. We observed a significant increase in cellular density, nucleic acid content, neutral lipid density, Collagen III, and glycosaminoglycans in regenerative skin compared with reparative skin. Additionally, regenerative skin had significantly higher porosity, metabolic activity, water absorption capacity, and elasticity than reparative skin. Finally, our results also revealed significant differences in lipid distribution, extracellular matrix pore size, and proteoglycans between the two groups. This study provides comprehensive data on the molecular and structural clues that enable full tissue regeneration in fetal stages, which could aid in developing new biomaterials and strategies for tissue engineering and regeneration.

The liver is a central organ for the synthesis and storage of nutrients, production of serum proteins and hormones, and breakdown of toxins and metabolites. Because the liver is susceptible to toxin-or pathogen-mediated injury, it maintains a remarkable capacity to regenerate by compensatory growth. Specifically, in response to injury, quiescent hepatocytes enter the cell cycle and undergo DNA replication to promote liver regrowth. Despite the elucidation of a number of regenerative factors, the mechanisms by which liver injury triggers hepatocyte proliferation are incompletely understood. We demonstrate here that eosinophils stimulate liver regeneration after partial hepatectomy and toxin-mediated injury. Liver injury results in rapid recruitment of eosinophils, which secrete IL-4 to promote the proliferation of quiescent hepatocytes. Surprisingly, signaling via the IL-4Rα in macrophages, which have been implicated in tissue repair, is dispensable for hepatocyte proliferation and liver regrowth after injury. Instead, IL-4 exerts its proliferative actions via IL-4 Rot in hepatocytes. Our findings thus provide a unique mechanism by which eosinophil-derived IL-4 stimulates hepatocyte proliferation in regenerating liver.

The ability of the skin to repair itself after injury is vital to human survival and is disrupted in a spectrum of disorders. The process of cutaneous wound healing is complex, requiring a coordinated response by immune cells, hematopoietic cells, and resident cells of the skin. We review the classic paradigms of wound healing and evaluate how recent discoveries have enriched our understanding of this process. We evaluate current and experimental approaches to treating cutaneous wounds, with an emphasis on cell-based therapies and skin transplantation.

Mesenchymal stem cells (MSCs) are isolated from multiple biological tissues—adult bone marrow and adipose tissues and neonatal tissues such as umbilical cord and placenta. In vitro, MSCs show biological features of extensive proliferation ability and multipotency. Moreover, MSCs have trophic, homing/migration and immunosuppression functions that have been demonstrated both in vitro and in vivo. A number of clinical trials are using MSCs for therapeutic interventions in severe degenerative and/or inflammatory diseases, including Crohn’s disease and graft-versus-host disease, alone or in combination with other drugs. MSCs are promising for therapeutic applications given the ease in obtaining them, their genetic stability, their poor immunogenicity and their curative properties for tissue repair and immunomodulation. The success of MSC therapy in degenerative and/or inflammatory diseases might depend on the robustness of the biological functions of MSCs, which should be linked to their therapeutic potency. Here, we outline the fundamental and advanced concepts of MSC biological features and underline the biological functions of MSCs in their basic and translational aspects in therapy for degenerative and/or inflammatory diseases.

Significance This study addresses a fundamentally important and widely debated issue in the field of inflammation, which is why inflammation can be simultaneously deleterious after injury and yet is essential for tissue repair. Recently, an important new paradigm has emerged in the macrophage field: Organs are replete with resident macrophages of embryonic origin, distinct from monocyte-derived macrophages. In this article, we use a new model of cardiac injury and show that distinct macrophage populations derived from embryonic and adult lineages are important determinants of tissue repair and inflammation, respectively. Our data suggest that therapeutics, which inhibit monocyte-derived macrophages and/or selectively harness the function of embryonic-derived macrophages, may serve as novel treatments for heart failure. The mechanistic basis for why inflammation is simultaneously both deleterious and essential for tissue repair is not fully understood. Recently, a new paradigm has emerged: Organs are replete with resident macrophages of embryonic origin distinct from monocyte-derived macrophages. This added complexity raises the question of whether distinct immune cells drive inflammatory and reparative activities after injury. Previous work has demonstrated that the neonatal heart has a remarkable capacity for tissue repair compared with the adult heart, offering an ideal context to examine these concepts. We hypothesized that unrecognized differences in macrophage composition is a key determinant of cardiac tissue repair. Using a genetic model of cardiomyocyte ablation, we demonstrated that neonatal mice expand a population of embryonic-derived resident cardiac macrophages, which generate minimal inflammation and promote cardiac recovery through cardiomyocyte proliferation and angiogenesis. During homeostasis, the adult heart contains embryonic-derived macrophages with similar properties. However, after injury, these cells were replaced by monocyte-derived macrophages that are proinflammatory and lacked reparative activities. Inhibition of monocyte recruitment to the adult heart preserved embryonic-derived macrophage subsets, reduced inflammation, and enhanced tissue repair. These findings indicate that embryonic-derived macrophages are key mediators of cardiac recovery and suggest that therapeutics targeting distinct macrophage lineages may serve as novel treatments for heart failure.

Tissue engineering and regenerative medicine (TERM) holds great promise for addressing the growing need for innovative therapies to treat disease conditions. To achieve this, TERM relies on various strategies and techniques. The most prominent strategy is the development of a scaffold. Polyvinyl alcohol-chitosan (PVA-CS) scaffold emerged as a promising material in this field due to its biocompatibility, versatility, and ability to support cell growth and tissue regeneration. Preclinical studies showed that the PVA-CS scaffold can be fabricated and tailored to fit the specific needs of different tissues and organs. Additionally, PVA-CS can be combined with other materials and technologies to enhance its regenerative capabilities. Furthermore, PVA-CS represents a promising therapeutic solution for developing new and innovative TERM therapies. Therefore, in this review, we summarized the potential role and functions of PVA-CS in TERM applications.