Teriparatide Promotes Bone Marrow Mesenchymal Stem Cells (BMSCs) Proliferation and Differentiation via Down-Regulating miR-298

This study explored whether teriparatide promotes BMSCs proliferation and differentiation via downregulating miR-298 and provided a basis for bone repair. Based on the microarray analysis after teriparatide treatment, qRT-PCR verified the differentially expressed miRNAs and the osteogenic differentiation was assessed by transfection of miRNA overexpression plasmids and miRNA inhibitors. miRNA array analysis and qRT-PCR verification showed that miR-298 was significantly downregulated during teriparatide-induced BMSCs differentiation. miR-298 overexpression significantly inhibited ALP and OPN expression which was promoted by transfection of miR-298 inhibitor. miR-298 is a negative regulator of BMSCs differentiation induced by teriparatide. Dlx5 is the target of miR-298. Inhibition of DLX5 expression by miR-298 was involved in the osteogenic differentiation of BMSCs. In conclusion, miR-298 negatively regulates the differentiation of BMSCs induced by teriparatide by targeting DLX5, providing a possible therapeutic target for bone tissue repair and regeneration.

Therapeutic Mesenchymal Stem/Stromal Cells: Value, Challenges and Optimization

Cellular therapy aims to replace damaged resident cells by restoring cellular and molecular environments suitable for tissue repair and regeneration. Among several candidates, mesenchymal stem/stromal cells (MSCs) represent a critical component of stromal niches known to be involved in tissue homeostasis. In vitro, MSCs appear as fibroblast-like plastic adherent cells regardless of the tissue source. The therapeutic value of MSCs is being explored in several conditions, including immunological, inflammatory and degenerative diseases, as well as cancer. An improved understanding of their origin and function would facilitate their clinical use. The stemness of MSCs is still debated and requires further study. Several terms have been used to designate MSCs, although consensual nomenclature has yet to be determined. The presence of distinct markers may facilitate the identification and isolation of specific subpopulations of MSCs. Regarding their therapeutic properties, the mechanisms underlying their immune and trophic effects imply the secretion of various mediators rather than direct cellular contact. These mediators can be packaged in extracellular vesicles, thus paving the way to exploit therapeutic cell-free products derived from MSCs. Of importance, the function of MSCs and their secretome are significantly sensitive to their environment. Several features, such as culture conditions, delivery method, therapeutic dose and the immunobiology of MSCs, may influence their clinical outcomes. In this review, we will summarize recent findings related to MSC properties. We will also discuss the main preclinical and clinical challenges that may influence the therapeutic value of MSCs and discuss some optimization strategies.

A Polyhydroxyalkanoates-Based Carrier Platform of Bioactive Substances for Therapeutic Applications

Bioactive substances (BAS), such as small molecule drugs, proteins, RNA, cells, etc., play a vital role in many therapeutic applications, especially in tissue repair and regeneration. However, the therapeutic effect is still a challenge due to the uncontrollable release and instable physico-chemical properties of bioactive components. To address this, many biodegradable carrier systems of micro-nano structures have been rapidly developed based on different biocompatible polymers including polyhydroxyalkanoates (PHA), the microbial synthesized polyesters, to provide load protection and controlled-release of BAS. We herein highlight the developments of PHA-based carrier systems in recent therapeutic studies, and give an overview of its prospective applications in various disease treatments. Specifically, the biosynthesis and material properties of diverse PHA polymers, designs and fabrication of micro- and nano-structure PHA particles, as well as therapeutic studies based on PHA particles, are summarized to give a comprehensive landscape of PHA-based BAS carriers and applications thereof. Moreover, recent efforts focusing on novel-type BAS nano-carriers, the functionalized self-assembled PHA granules in vivo, was discussed in this review, proposing the underlying innovations of designs and fabrications of PHA-based BAS carriers powered by synthetic biology. This review outlines a promising and applicable BAS carrier platform of novelty based on PHA particles for different medical uses.

Efficacy of platelet-rich plasma lysate in the treatment of patients with post-traumatic eyelid scarring: an overview of clinical cases

Purpose: to evaluate the effectiveness of platelet-rich plasma lysate (PRP) in the treatment of patients with post-traumatic eyelid scarring by clinical examples. Material and methods. Patients with post-traumatic scarring changes in eyelid tissues causing a damage in the functional and cosmetic state of the auxiliary apparatus of the eye were treated in the Department of Plastic Surgery and Eye Prosthetics at the Helmholtz National Medical Research Center of Eye Diseases. Two of the patients, who had been traumatized shortly before the examination and one patient who had rejected surgery were offered treatment by PRP lysate manufactured at the Sklifosovsky Medical Research Institute of Emergency Medicine. After local infiltration anesthesia, each patient received a single injection of PRP lysate (2 ml) into the scar tissue. The result was evaluated at a follow-up that took place 3 months after the injection. Results. The clinical picture of the three patients showed a pronounced positive dynamic of the functional and cosmetic state of the auxiliary eye apparatus, which made the patients reject subsequent (additional) surgical treatment. Conclusion. An improvement tissue repair and regeneration processes after PRP lysate injection allows us to assess this method as an applicable alternative of reconstructive operations in certain cases.

Amniotic Fluid-derived MSC Secretome Halts Action of IL-1β and TNF-α Through ERK/MAPK and Returns Cartilage Repair Under OA Inflammatory Stimuli

Background: Osteoarthritis (OA) is a degenerative cartilage disease. OA cartilage has a limited repair capacity due to the effect of IL-1β and TNF-α on the chondrocyte progenitor cells (CPC) in an OA joint. Mesenchymal stem cells (MSC) therapy is a therapeutic option for osteoarthritis that initiated by the ability of secretory growth factors and mediator molecules to heal OA. Amniotic fluid MSC (AF-MSC), an interesting MSC source, has been shown to secrete various growth factors and anti-inflammatory molecules promoting tissue repair and regeneration. However, the effect of AF-MSC secretory factors to inflammation and cartilage repair is still limited. The current study aims to explore the action of AF-MSC secretome to IL-1β and TNF-α, and the CPC function that encourages cartilage repair.Methods: The effect of AF-MSC secretome to OA inflammatory cytokines was observed via the CPC migration using scratch assay. Inhibitory action of AF-MSC secretome to IL-1β and TNF-α was determined through NF-κB and MAPK signaling pathways by western blot. The repaired function of OA cartilage was analyzed via the cartilage outgrowth study and the expression of chondrogenic and anabolic genes using qRT-PCR.Results: AF-MSC secretome can arrest inflammatory action of IL-1β and TNF-α and reduces production of NF-κB, pNF-κB, p38, pp38, ERK, COX-2, and iNOS signaling proteins. It significantly reduced the production of pERK (P = 0.0434). For cartilage repair, AF-MSC secretome promotes CPC outgrowth and migration in human OA cartilage, even under inflammatory stimuli. By the action of AF-MSC secretome, the inflamed CPC can restore Col II and anabolic genes; IGF1 expression, indicating reactivation of cartilage regeneration.Conclusion: AF-MSC secretory factors have the ability to halt inflammatory actions of IL-1β and TNF-α via the ERK/MAPK pathway and motivate CPC function and anabolic property.

Fibronectin-Enriched Biomaterials, Biofunctionalization, and Proactivity: A Review

Modern innovation in reconstructive medicine implies the proposition of material-based strategies suitable for tissue repair and regeneration. The development of such systems necessitates the design of advanced materials and the control of their interactions with their surrounding cellular and molecular microenvironments. Biomaterials must actively engage cellular matter to direct and modulate biological responses at implant sites and beyond. Indeed, it is essential that a true dialogue exists between the implanted device and the cells. Biomaterial engineering implies the knowledge and control of cell fate considering the globality of the adhesion process, from initial cell attachment to differentiation. The extracellular matrix (ECM) represents a complex microenvironment able to meet these essential needs to establish a relationship between the material and the contacting cells. The ECM exhibits specific physical, chemical, and biochemical characteristics. Considering the complexity, heterogeneity, and versatility of ECM actors, fibronectin (Fn) has emerged among the ECM protagonists as the most pertinent representative key actor. The following review focuses on and synthesizes the research supporting the potential to use Fn in biomaterial functionalization to mimic the ECM and enhance cell–material interactions.

Three-Dimensional Porous Scaffolds Derived from Bovine Cancellous Bone Matrix Promote Osteoinduction, Osteoconduction, and Osteogenesis

The use of three-dimensional porous scaffolds derived from decellularized extracellular matrix (ECM) is increasing for functional repair and regeneration of injured bone tissue. Because these scaffolds retain their native structures and bioactive molecules, in addition to showing low immunogenicity and good biodegradability, they can promote tissue repair and regeneration. Nonetheless, imitating these features in synthetic materials represents a challenging task. Furthermore, due to the complexity of bone tissue, different processes are necessary to maintain these characteristics. We present a novel approach using decellularized ECM material derived from bovine cancellous bone by demineralization, decellularization, and hydrolysis of collagen to obtain a three-dimensional porous scaffold. This study demonstrates that the three-dimensional porous scaffold obtained from bovine bone retained its osteoconductive and osteoinductive properties and presented osteogenic potential when seeded with human Wharton’s jelly mesenchymal stromal cells (hWJ-MSCs). Based on its characteristics, the scaffold described in this work potentially represents a therapeutic strategy for bone repair.

Therapeutic Opportunities of IL-22 in Non-Alcoholic Fatty Liver Disease: From Molecular Mechanisms to Clinical Applications

Nonalcoholic fatty liver disease (NAFLD) represents one of the most common liver disorders and can progress into a series of liver diseases, including nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and even liver cancer. Interleukin-22 (IL-22), a member of the IL-10 family of cytokines, is predominantly produced by lymphocytes but acts exclusively on epithelial cells. IL-22 was proven to favor tissue protection and regeneration in multiple diseases. Emerging evidence suggests that IL-22 plays important protective functions against NAFLD by improving insulin sensitivity, modulating lipid metabolism, relieving oxidative and endoplasmic reticulum (ER) stress, and inhibiting apoptosis. By directly interacting with the heterodimeric IL-10R2 and IL-22R1 receptor complex on hepatocytes, IL-22 activates the Janus kinase 1 (JAK1)/ signal transducer and activator of transcription 3 (STAT3), c-Jun N-terminal kinase (JNK) and extracellular-signal regulated kinase (ERK) pathways to regulate the subsequent expression of genes involved in inflammation, metabolism, tissue repair, and regeneration, thus alleviating hepatitis and steatosis. However, due to the wide biodistribution of the IL-22 receptor and its proinflammatory effects, modifications such as targeted delivery of IL-22 expression and recombinant IL-22 fusion proteins to improve its efficacy while reducing systemic side effects should be taken for further clinical application. In this review, we summarized recent progress in understanding the physiological and pathological importance of the IL-22-IL-22R axis in NAFLD and the mechanisms of IL-22 in the protection of NAFLD and discussed the potential strategies to maneuver this specific cytokine for therapeutic applications for NAFLD.

Bio-Scaffolds as Cell or Exosome Carriers for Nerve Injury Repair

Central and peripheral nerve injuries can lead to permanent paralysis and organ dysfunction. In recent years, many cell and exosome implantation techniques have been developed in an attempt to restore function after nerve injury with promising but generally unsatisfactory clinical results. Clinical outcome may be enhanced by bio-scaffolds specifically fabricated to provide the appropriate three-dimensional (3D) conduit, growth-permissive substrate, and trophic factor support required for cell survival and regeneration. In rodents, these scaffolds have been shown to promote axonal regrowth and restore limb motor function following experimental spinal cord or sciatic nerve injury. Combining the appropriate cell/exosome and scaffold type may thus achieve tissue repair and regeneration with safety and efficacy sufficient for routine clinical application. In this review, we describe the efficacies of bio-scaffolds composed of various natural polysaccharides (alginate, chitin, chitosan, and hyaluronic acid), protein polymers (gelatin, collagen, silk fibroin, fibrin, and keratin), and self-assembling peptides for repair of nerve injury. In addition, we review the capacities of these constructs for supporting in vitro cell-adhesion, mechano-transduction, proliferation, and differentiation as well as the in vivo properties critical for a successful clinical outcome, including controlled degradation and re-absorption. Finally, we describe recent advances in 3D bio-printing for nerve regeneration.

Hepatocyte Growth Factor-Preconditioned Neural Progenitor Cells Attenuate Astrocyte Reactivity and Promote Neurite Outgrowth

The astroglial scar is a defining hallmark of secondary pathology following central nervous system (CNS) injury that, despite its role in limiting tissue damage, presents a significant barrier to neuroregeneration. Neural progenitor cell (NPC) therapies for tissue repair and regeneration have demonstrated favorable outcomes, the effects of which are ascribed not only to direct cell replacement but trophic support. Cytokines and growth factors secreted by NPCs aid in modifying the inhibitory and cytotoxic post-injury microenvironment. In an effort to harness and enhance the reparative potential of NPC secretome, we utilized the multifunctional and pro-regenerative cytokine, hepatocyte growth factor (HGF), as a cellular preconditioning agent. We first demonstrated the capacity of HGF to promote NPC survival in the presence of oxidative stress. We then assessed the capacity of this modified conditioned media (CM) to attenuate astrocyte reactivity and promote neurite outgrowth in vitro. HGF pre-conditioned NPCs demonstrated significantly increased levels of tissue inhibitor of metalloproteinases-1 and reduced vascular endothelial growth factor compared to untreated NPCs. In reactive astrocytes, HGF-enhanced NPC-CM effectively reduced glial fibrillary acidic protein (GFAP) expression and chondroitin sulfate proteoglycan deposition to a greater extent than either treatment alone, and enhanced neurite outgrowth of co-cultured neurons. in vivo, this combinatorial treatment strategy might enable tactical modification of the post-injury inhibitory astroglial environment to one that is more conducive to regeneration and functional recovery. These findings have important translational implications for the optimization of current cell-based therapies for CNS injury.