Self-regenerative Capacity Research Articles

Direct in vivo cardiac reprogramming with circular RNA of single transcription factor delivered by fibroblast-targeting lipid nanoparticles

Abstract Background Adult mammalian cardiomyocytes (CMs) hold limited capacity for self-regeneration, thus leading to permanent loss of functional myocardium once suffering from injury, especially myocardial infarction (MI). Therefore, cardiac regeneration therapy has been regarded as a potential path to help restore damaged tissue. Direct cardiac reprogramming is one of the most promising ways to boost cardiac regeneration as it could convert resident cardiac fibroblasts into functional induced cardiomyocytes (iCMs). However, difficulty of delivery has been one of the biggest problems that hinder the further clinical translation of this technique such as concerns of mostly used retrovirus vectors and lack of fibroblast-specific targeting ability. In our previous research, we have found that after knocking down of Ybx1 gene, single transcriptional factor Tbx5 could induce cardiac reprogramming of fibroblasts without adding traditional Mef2c and Gata4. But whether this cocktail could achieve in vivo direct cardiac reprogramming still remains to be explored. Objective We planned to develop fibroblast-targeting lipid nanoparticles (LNP) to delivery circular RNA(circRNA) of Tbx5 and small interfering RNA(siRNA) of Ybx1 to realize in vivo cardiac reprogramming in a mouse model of myocardial infarction. Results We first screened different formulations of tdTomato mRNA delivered-LNP both in primary neonatal cardiac fibroblasts and in the myocardial infarction model and found that formulation XF4d could realize specific selectively uptake by cardiac fibroblasts instead of cardiomyocytes. Then we succeeded in synthesizing XF4d LNP delivering Tbx5 circRNA and Ybx1 siRNA (LNPXF4d@Tbx5+siYbx1) and validated its stability at 4°C. Next, after infecting LNPXF4d@Tbx5+siYbx1, primary neonatal CFs and mouse embryonic fibroblasts could be reprogrammed into functional iCMs. We further measured the protein expression of Tbx5 and Ybx1 in CFs after LNPXF4d@Tbx5+siYbx1 treatment. What’s more, we used fibroblast-specific lineage tracing mice (Fsp1Cre/tdTomato mice) to prove the successful conversion of resident CFs into iCMs in the mouse model of myocardial infarction by intramyocardial injection of LNPXF4d@Tbx5+siYbx1. At last, we found that LNPXF4d@Tbx5+siYbx1 could help improve cardiac function after injury and reduce fibrosis, as measured by echocardiography and Masson’s trichrome staining. Conclusion We suggest that our fibroblast specific LNPs delivering single transcriptional factors could a promising method to realize in vivo cardiac reprogramming and help treat myocardial injury, with high possibility of clinical translation and less biosafety concerns.Graphical Abstract

Osteogenic Potential and Long-Term Enzymatic Biodegradation of PHB-based Scaffolds with Composite Magnetic Nanofillers in a Magnetic Field.

Millions of people worldwide suffer from musculoskeletal damage, thus using the largest proportion of rehabilitation services. The limited self-regenerative capacity of bone and cartilage tissues necessitates the development of functional biomaterials. Magnetoactive materials are a promising solution due to clinical safety and deep tissue penetration of magnetic fields (MFs) without attenuation and tissue heating. Herein, electrospun microfibrous scaffolds were developed based on piezoelectric poly(3-hydroxybutyrate) (PHB) and composite magnetic nanofillers [magnetite with graphene oxide (GO) or reduced GO]. The scaffolds' morphology, structure, mechanical properties, surface potential, and piezoelectric response were systematically investigated. Furthermore, a complex mechanism of enzymatic biodegradation of these scaffolds is proposed that involves (i) a release of polymer crystallites, (ii) crystallization of the amorphous phase, and (iii) dissolution of the amorphous phase. Incorporation of Fe3O4, Fe3O4-GO, or Fe3O4-rGO accelerated the biodegradation of PHB scaffolds owing to pores on the surface of composite fibers and the enlarged content of polymer amorphous phase in the composite scaffolds. Six-month biodegradation caused a reduction in surface potential (1.5-fold) and in a vertical piezoresponse (3.5-fold) of the Fe3O4-GO scaffold because of a decrease in the PHB β-phase content. In vitro assays in the absence of an MF showed a significantly more pronounced mesenchymal stem cell proliferation on composite magnetic scaffolds compared to the neat scaffold, whereas in an MF (68 mT, 0.67 Hz), cell proliferation was not statistically significantly different when all the studied scaffolds were compared. The PHB/Fe3O4-GO scaffold was implanted into femur bone defects in rats, resulting in successful bone repair after nonperiodic magnetic stimulation (200 mT, 0.04 Hz) owing to a synergetic influence of increased surface roughness, the presence of hydrophilic groups near the surface, and magnetoelectric and magnetomechanical effects of the material.

Hydrogel-Based 3D Bioprinting Technology for Articular Cartilage Regenerative Engineering.

Articular cartilage is an avascular tissue with very limited capacity of self-regeneration. Trauma or injury-related defects, inflammation, or aging in articular cartilage can induce progressive degenerative joint diseases such as osteoarthritis. There are significant clinical demands for the development of effective therapeutic approaches to promote articular cartilage repair or regeneration. The current treatment modalities used for the repair of cartilage lesions mainly include cell-based therapy, small molecules, surgical approaches, and tissue engineering. However, these approaches remain unsatisfactory. With the advent of three-dimensional (3D) bioprinting technology, tissue engineering provides an opportunity to repair articular cartilage defects or degeneration through the construction of organized, living structures composed of biomaterials, chondrogenic cells, and bioactive factors. The bioprinted cartilage-like structures can mimic native articular cartilage, as opposed to traditional approaches, by allowing excellent control of chondrogenic cell distribution and the modulation of biomechanical and biochemical properties with high precision. This review focuses on various hydrogels, including natural and synthetic hydrogels, and their current developments as bioinks in 3D bioprinting for cartilage tissue engineering. In addition, the challenges and prospects of these hydrogels in cartilage tissue engineering applications are also discussed.

The Transformation and Utilization of Non-material Resources by First-Generation College Students

The growth issues of first-generation college students have always been a focus of attention. This study delves into the subtle interactions and relationships that underlie the non-material resources, encompassing moral emotions and other intrinsic elements associated with the self, which are predicated upon material capital. Through the interpretation of the significance of case study and textual analysis method, we have uncovered the value of immaterial resources as “potential” in some sense, manifesting as an integration of the values of multi-dimensional interconnection and self-subjectivity. The study outlines actionable strategies to help first-generation college students utilize non-material resources across three distinct dimensions: family communication, cultural reinvestment, and self-regenerative capacity.

M2 Macrophage-Derived Small Extracellular Vesicles Ameliorate Pyroptosis and Intervertebral Disc Degeneration.

Intervertebral discs (IVDs) have a limited self-regenerative capacity and current strategies for IVD regeneration are unsatisfactory. Recent studies showed that small extracellular vesicles derived from M2 macrophage cells (M2-sEVs) inhibited inflammation by delivery of various bioactive molecules to recipient cells, which indicated that M2-sEVs may offer a therapeutic strategy for the repair of IVDs. Herein, we investigated the roles and mechanisms of M2-sEVs on IVD regeneration. The invitro results demonstrated that M2-sEVs inhibited pyroptosis, preserved cellular viability, and promoted migration of nucleus pulposus cells (NPCs). Bioinformatics analysis and verification experiments of microRNA (miR) expression showed that miR-221-3p was highly expressed in M2-sEVs. The mechanism of action was explored and indicated that M2-sEVs inhibited pyroptosis of NPCs through transfer of miR-221-3p, which suppressed the expression levels of phosphatase and tensin homolog and NOD-, LRR-, and pyrin domain-containing protein 3. Moreover, we fabricated decellularized ECM-hydrogel (dECM) for sustained release of M2-sEVs, which exhibited biocompatibility and controlled release properties. The invivo results revealed that dECM-hydrogel containing M2-sEVs (dECM/M2-sEVs) delayed the degeneration of intervertebral disc degeneration (IDD) models. In addition to demonstrating a promising therapeutic for IDD, this study provided valuable data for furthering the understanding of the roles and mechanisms of M2-sEVs in IVD regeneration.

Advanced Hydrogel-Based Strategies for Enhanced Bone and Cartilage Regeneration: A Comprehensive Review.

Bone and cartilage tissue play multiple roles in the organism, including kinematic support, protection of organs, and hematopoiesis. Bone and, above all, cartilaginous tissues present an inherently limited capacity for self-regeneration. The increasing prevalence of disorders affecting these crucial tissues, such as bone fractures, bone metastases, osteoporosis, or osteoarthritis, underscores the urgent imperative to investigate therapeutic strategies capable of effectively addressing the challenges associated with their degeneration and damage. In this context, the emerging field of tissue engineering and regenerative medicine (TERM) has made important contributions through the development of advanced hydrogels. These crosslinked three-dimensional networks can retain substantial amounts of water, thus mimicking the natural extracellular matrix (ECM). Hydrogels exhibit exceptional biocompatibility, customizable mechanical properties, and the ability to encapsulate bioactive molecules and cells. In addition, they can be meticulously tailored to the specific needs of each patient, providing a promising alternative to conventional surgical procedures and reducing the risk of subsequent adverse reactions. However, some issues need to be addressed, such as lack of mechanical strength, inconsistent properties, and low-cell viability. This review describes the structure and regeneration of bone and cartilage tissue. Then, we present an overview of hydrogels, including their classification, synthesis, and biomedical applications. Following this, we review the most relevant and recent advanced hydrogels in TERM for bone and cartilage tissue regeneration.

Transforming Perspectives in Cardiac Cell Therapy: Hypothesis and Commentary Following Updated Results of a Pilot Study Investigating Very Long-Term Clinical Outcomes in Severe AMI Patients Following Trans-Epicardial Injection of Peripheral Blood CD34+ Cells

Ischemic heart attack is the leading cause of death worldwide. Ten percent of cases will die within an hour. Of the survivors, around 30% will have suffered a severe infarction which will lead to the irreparable destruction of 1 to 2 billion myocardial cells, causing an irreversible secondary heart failure with a poor prognosis in the short. The heart is a totally differentiated organ with a very low capacity for self-regeneration. No current treatment can prevent this fatal outcome, but only slow it down. For these reasons, cell therapy has generated enormous hope, but achieved somewhat disappointing results, depending on the type/source of cells which were used. From the end of 2002, our group conducted a Pilot study using immuno-selected autologous peripheral-blood (PB) CD34+ cells in a small cohort of patients who had experienced a heart attack with poor prognosis. Three of these patients were immediately considered for heart transplant but lacked a readily available donor. CD34+ cells were trans-epicardially delivered at the end of a coronary artery by-pass graft (CABG) operation without reperfusing the ischemic area, which was performed on a compassionate basis. All but one patient showed a marked and sustained improvement in their cardiac function parameters from the baseline values, associated with both cardiac tissue repair and revascularization, as demonstrated by PetScan examination. The patients’ outcomes have been recently updated. Six out of seven patients have survived in good enough conditions for at least 12 years after cell therapy, including those three initially recommended for heart transplant and who have avoided it. Presently, five out of seven patients are still alive with an average follow-up of 17 years (range 16–20 years), which is very unusual after CABG for patients with such a poor initially prognosis.Graphical

Menstrual Blood-Derived Stem Cell Paracrine Factors Possess Stimulatory Effects on Chondrogenesis In Vitro and Diminish the Degradation of Articular Cartilage during Osteoarthritis.

Articular cartilage is an avascular tissue with a limited capacity for self-regeneration, leading the tissue to osteoarthritis (OA). Mesenchymal stem cells (MSCs) are promising for cartilage tissue engineering, as they are capable of differentiating into chondrocyte-like cells and secreting a number of active molecules that are important for cartilage extracellular matrix (ECM) synthesis. The aim of this study was to evaluate the potential of easily accessible menstrual blood-derived MSC (MenSC) paracrine factors in stimulating bone marrow MSC (BMMSCs) chondrogenic differentiation and to investigate their role in protecting cartilage from degradation in vitro. MenSCs and BMMSCs chondrogenic differentiation was induced using four different growth factors: TGF-β3, activin A, BMP-2, and IGF-1. The chondrogenic differentiation of BMMSCs was stimulated in co-cultures with MenSCs and cartilage explants co-cultured with MenSCs for 21 days. The chondrogenic capacity of BMMSCs was analyzed by the secretion of four growth factors and cartilage oligomeric matrix protein, as well as the release and synthesis of cartilage ECM proteins, and chondrogenic gene expression in cartilage explants. Our results suggest that MenSCs stimulate chondrogenic response in BMMSCs by secreting activin A and TGF-β3 and may have protective effects on cartilage tissue ECM by decreasing the release of GAGs, most likely through the modulation of activin A related molecular pathway. In conclusion, paracrine factors secreted by MenSCs may turn out to be a promising therapeutical approach for cartilage tissue protection and repair.

Bioengineered human tissue regeneration and repair using endogenous stem cells

We describe a general approach to produce bone and cartilaginous structures utilizing the self-regenerative capacity of the intercostal rib space to treat a deformed metacarpophalangeal joint and microtia. Anatomically precise 3D molds were positioned on the perichondro-periosteal or perichondral flap of the intercostal rib without any other exogenous elements. We find anatomically precise metacarpal head and auricle constructs within the implanted molds after 6months. The regenerated metacarpal head was used successfully to surgically repair the deformed metacarpophalangeal joint. Auricle reconstructive surgery in five unilateral microtia patients yielded good aesthetic and functional results. Long-term follow-up revealed the auricle constructs were safe and stable. Single-cell RNA sequencing analysis reveal early infiltration of a cell population consistent with mesenchymal stem cells, followed by IL-8-stimulated differentiation into chondrocytes. Our results demonstrate the repair and regeneration of tissues using only endogenous factors and a viable treatment strategy for bone and tissue structural defects.

Harnessing Biofabrication Strategies to Re-Surface Osteochondral Defects: Repair, Enhance, and Regenerate.

Osteochondral tissue (OC) is a complex and multiphasic system comprising cartilage and subchondral bone. The discrete OC architecture is layered with specific zones characterized by different compositions, morphology, collagen orientation, and chondrocyte phenotypes. To date, the treatment of osteochondral defects (OCD) remains a major clinical challenge due to the low self-regenerative capacity of damaged skeletal tissue, as well as the critical lack of functional tissue substitutes. Current clinical approaches fail to fully regenerate damaged OC recapitulating the zonal structure while granting long-term stability. Thus, the development of new biomimetic treatment strategies for the functional repair of OCDs is urgently needed. Here, we review recent developments in the preclinical investigation of novel functional approaches for the resurfacing of skeletal defects. The most recent studies on preclinical augmentation of OCDs and highlights on novel studies for the in vivo replacement of diseased cartilage are presented.

Hypoxia Differentially Affects Chondrogenic Differentiation of Progenitor Cells from Different Origins.

Ear cartilage malformations are commonly encountered problems in reconstructive surgery, since cartilage has low self-regenerating capacity. Malformations that impose psychological and social burden on one's life are currently treated using ear prosthesis, synthetic implants or autologous flaps from rib cartilage. These approaches are challenging because not only they request high surgical expertise, but also they lack flexibility and induce severe donor-site morbidity. Through the last decade, tissue engineering gained attention where it aims at regenerating human tissues or organs in order to restore normal functions. This technique consists of three main elements, cells, growth factors, and above all, a scaffold that supports cells and guides their behavior. Several studies have investigated different scaffolds prepared from both synthetic or natural materials and their effects on cellular differentiation and behavior. In this study, we investigated a natural scaffold (alginate) as tridimensional hydrogel seeded with progenitors from different origins such as bone marrow, perichondrium and dental pulp. In contact with the scaffold, these cells remained viable and were able to differentiate into chondrocytes when cultured in vitro. Quantitative and qualitative results show the presence of different chondrogenic markers as well as elastic ones for the purpose of ear cartilage, upon different culture conditions. We confirmed that auricular perichondrial cells outperform other cells to produce chondrogenic tissue in normal oxygen levels and we report for the first time the effect of hypoxia on these cells. Our results provide updates for cartilage engineering for future clinical applications.

Marine collagen-chitosan-fucoidan/chondroitin sulfate cryo-biomaterials loaded with primary human cells envisaging cartilage tissue engineering

Cartilage repair after a trauma or a degenerative disease like osteoarthritis (OA) continues to be a big challenge in current medicine due to the limited self-regenerative capacity of the articular cartilage tissues. To overcome the current limitations, tissue engineering and regenerative medicine (TERM) and adjacent areas have focused their efforts on new therapeutical procedures and materials capable of restoring normal tissue functionalities through polymeric scaffolding and stem cell engineering approaches. For this, the sustainable exploration of marine origin materials has emerged in the last years as a natural alternative to mammal sources, benefiting from their biological properties (e.g., biocompatibility, biodegradability, no toxicity, among others) for the development of several types of scaffolds. In this study, marine collagen(jCOL)-chitosan(sCHT)-fucoidan(aFUC)/chondroitin sulfate(aCS) were cryo-processed (−20 °C, −80 °C, and −196 °C) and a chemical-free crosslinking approach was explored to establish cohesive and stable cryogel materials. The cryogels were intensively characterized to assess their oscillatory behavior, thermal structural stability, thixotropic properties (around 45 % for the best formulations), injectability, and surface structural organization. Additionally, the cryogels demonstrate an interesting microenvironment in in vitro studies using human adipose-derived stem cells (hASCs), supporting their viability and proliferation. In both physic-chemical and in vitro studies, the systems that contain fucoidan in their formulations, i.e., C1 (jCOL, sCHT, aFUC) and C3 (jCOL, sCHT, aFUC, aCS), submitted at −80 °C, are those that demonstrated most promising results for future application in articular cartilage tissues.

Optimization of thermoresponsive chitosan/β-glycerophosphate hydrogels for injectable neural tissue engineering application

Regeneration of neural tissue and recovery of lost functions following an accident or disease to the central nervous system remains a major challenge worldwide, with limited treatment options available. The main reason for the failure of conventional therapeutic techniques to regenerate neural tissue is the presence of blood-brain barrier separating nervous system from systemic circulation and the limited capacity of self-regeneration of the nervous system. Injectable hydrogels have shown great promise for neural tissue engineering given their suitability for minimally invasive in situ delivery and tunable mechanical and biological properties. Chitosan (CS)/β-glycerophosphate (β-GP) hydrogels have been extensively investigated and shown regenerative potential in a wide variety of tissues such as bone and cartilage tissue engineering. However, the potential of CS/β-GP hydrogels has never been tested for injectable neural tissue engineering applications. In the present study, CS/β-GP hydrogels, consisting of 0.5–2% CS and 2–3% β-GP, were prepared and characterized to investigate their suitability for injectable neural tissue engineering applications. The resulting CS/β-GP-hydrogels showed a varying range of properties depending on the CS/β-GP blend ratio. In particular, the 0.5%:3% and 0.75%:3% CS/β-GP hydrogels underwent rapid gelation (3 min and 5 min, respectively) at physiological temperature (37 °C) and pH (7.4). They also had suitable porosity, osmolality, swelling behavior and biodegradation for tissue engineering. The biocompatibility of hydrogels was determined in vitro using PC12 cells, an immortalized cell line with neuronal cell-like properties, revealing that these hydrogels supported cell growth and proliferation. In conclusion, the thermoresponsive 0.5%:3% and 0.75%:3% CS/β-GP hydrogels had the greatest potential for neural tissue engineering.

Collagen Fibril Diameter Distribution of Sheep Anterior Cruciate Ligament.

The anterior cruciate ligament (ACL) tissue is a soft tissue connecting the femur and tibia at the knee joint and demonstrates a limited capacity for self-regeneration due to its low vascularity. The currently available clinical procedures are unable to fully restore damaged ACL tissue, and tissue engineering can offer options with a potential of restoring the torn/ruptured ACL by using biomimetic constructs that are similar to native tissue in terms of structure, composition, and functions. However, a model substrate to understand how the ACL cells regenerate the injured tissue is still not available. In this study, it is hypothesized that the nanofiber-based model substrate with bimodal and unimodal fiber diameter distributions will mimic the diameter distribution of collagen fibrils seen in healthy and injured sheep ACL, respectively. The aims were to (i) create an ACL injury in a sheep ACL by applying extensional force to rupture the healthy ACL tissue, (ii) measure the collagen fibril diameter distributions of healthy and injured ACL, (iii) fabricate polycaprolactone (PCL) nanofiber-based model constructs using electrospinning with diameter distributions similar to healthy and injured ACL tissue, and (iv) measure mechanical properties of ACL tissue and PCL electrospun constructs. The results showed that the fiber diameter distributions of PCL electrospun constructs and those of the healthy and injured ACL tissues were similar. The novelty in this investigation is that the collagen fibril diameter distribution of healthy and injured sheep ACL tissues was reported for the first time. The study is significant because it aims to create a model construct to solve an important orthopedic-related clinical problem affecting millions of people globally. The model construct fabricated in this work is expected to have an important impact on ACL regeneration efforts.

Protection of Plant Biodiversity in the Light of International Law

Plants are an integral part of the living organism of nature. Protection of plant biodiversity is essential to ensure the health of ecosystems. The natural world is characterised by cyclical and mutually complementary processes. If the self-regenerative capacity of nature is disturbed, it results in a breach of the biological balance in the ecosystem and the human environment of life. The rapid degradation of natural habitats prompts one to analyse the existing plant protection mechanism. This paper will analyse environmental regulations and standards, which may be the basis for reforming protection programmes.

In Vivo Bone Tissue Engineering Strategies: Advances and Prospects.

Reconstruction of critical-sized bone defects remains a tremendous challenge for surgeons worldwide. Despite the variety of surgical techniques, current clinical strategies for bone defect repair demonstrate significant limitations and drawbacks, including donor-site morbidity, poor anatomical match, insufficient bone volume, bone graft resorption, and rejection. Bone tissue engineering (BTE) has emerged as a novel approach to guided bone tissue regeneration. BTE focuses on in vitro manipulations with seed cells, growth factors and bioactive scaffolds using bioreactors. The successful clinical translation of BTE requires overcoming a number of significant challenges. Currently, insufficient vascularization is the critical limitation for viability of the bone tissue-engineered construct. Furthermore, efficacy and safety of the scaffolds cell-seeding and exogenous growth factors administration are still controversial. The in vivo bioreactor principle (IVB) is an exceptionally promising concept for the in vivo bone tissue regeneration in a predictable patient-specific manner. This concept is based on the self-regenerative capacity of the human body, and combines flap prefabrication and axial vascularization strategies. Multiple experimental studies on in vivo BTE strategies presented in this review demonstrate the efficacy of this approach. Routine clinical application of the in vivo bioreactor principle is the future direction of BTE; however, it requires further investigation for overcoming some significant limitations.

Enhancing the function of PLGA-collagen scaffold by incorporating TGF-β1-loaded PLGA-PEG-PLGA nanoparticles for cartilage tissue engineering using human dental pulp stem cells.

Since cartilage has a limited capacity for self-regeneration, treating cartilage degenerative disorders is a long-standing difficulty in orthopedic medicine. Researchers have scrutinized cartilage tissue regeneration to handle the deficiency of cartilage restoration capacity. This investigation proposed to compose an innovative nanocomposite biomaterial that enhances growth factor delivery to the injured cartilage site. Here, we describe the design and development of the biocompatible poly(lactide-co-glycolide) acid-collagen/poly(lactide-co-glycolide)-poly(ethylene glycol)-poly(lactide-co-glycolide) (PLGA-collagen/PLGA-PEG-PLGA) nanocomposite hydrogel containing transforming growth factor-β1 (TGF-β1). PLGA-PEG-PLGA nanoparticles were employed as a delivery system embedding TGF-β1 as an articular cartilage repair therapeutic agent. This study evaluates various physicochemical aspects of fabricated scaffolds by 1HNMR, FT-IR, SEM, BET, and DLS methods. The physicochemical features of the developed scaffolds, including porosity, density, degradation, swelling ratio, mechanical properties, morphologies, BET, ELISA, and cytotoxicity were assessed. The cell viability was investigated with the MTT test. Chondrogenic differentiation was assessed via Alcian blue staining and RT-PCR. In real-time PCR testing, the expression of Sox-9, collagen type II, and aggrecan genes was monitored. According to the results, human dental pulp stem cells (hDPSCs) exhibited high adhesion, proliferation, and differentiation on PLGA-collagen/PLGA-PEG-PLGA-TGFβ1 nanocomposite scaffolds compared to the control groups. SEM images displayed suitable cell adhesion and distribution of hDPSCs throughout the scaffolds. RT-PCR assay data displayed that TGF-β1 loaded PLGA-PEG-PLGA nanoparticles puts forward chondroblast differentiation in hDPSCs through the expression of chondrogenic genes. The findings revealed that PLGA-collagen/PLGA-PEG-PLGA-TGF-β1 nanocomposite hydrogel can be utilized as a supportive platform to support hDPSCs differentiation by implementing specific physio-chemical features.

Gold Nanoclusters Potentially Facilitate Dentin Regeneration by Functioning Immunomodulation

It is presently difficult to achieve dental pulp vitality maintenance and regeneration in adult teeth. Dentin destruction results in the exposure of the dental pulp tissue to infectious oral environments, thereby triggering continuous severe pulp inflammation that impedes the self-regenerative capacity of the pulp. For these reasons, the regeneration of dentin bridges to block pulp tissue from the oral environment is an indispensable step. Nevertheless, this goal is difficult to achieve using present strategies, because the importance of immunoregulation in the pulp inflammatory microenvironment has been ignored. In our previous study, we found that the nanomaterial dihydrolipoic acid-functionalized gold nanoclusters (DHLA-AuNCs) efficiently regulated inflammatory responses in microglia (resident macrophages in the central nervous system), suggesting that DHLA-AuNCs may induce dentin bridge regeneration by regulating dental pulp macrophage responses. In the present study, we found that DHLA-AuNCs inhibited the M1 phenotype while promoting the M2 phenotype in macrophages in inflammatory conditions in vitro. This regulation of the inflammatory environment in dental pulp enhanced the differentiation of human dental pulp stromal cells (hDPC) toward odontoblasts, a beneficial effect on dentin regeneration. DHLA-AuNCs also had a direct role in the differentiation and mineralization of hDPC. These findings suggest that DHLA-AuNCs facilitate dentin regeneration through both efficient immunomodulation and direct induction of stromal cell differentiation/mineralization, providing a potential therapeutic nanomaterial for dentin bridge regeneration, effects that would be beneficial for dental pulp regeneration.

The Phoenix Complex

The Phoenix Complex

Mesenchymal stem cells and cell-free preparations for treating atopic dermatitis

Atopic dermatitis (AD) is a chronic cutaneous inflammatory disease caused by an interaction between genetic, immune and epidermal barrier factors. Several treatments can be used to treat this disease but there are patients that do not respond to actual drugs. So, there is a need to develop effective therapies for AD. Mesenchymal stem cells (MSCs) are non-hematopoietic multipotent adult progenitor cells with immunomodulatory power and self-regenerating capacity to repair tissue damage, so they could be a potential effective treatment for AD. MSCs-Conditioned Medium (CM) and MSCs-exosomes are cell-free preparation with molecules secreted by stem cells that could be also beneficial for AD. This viewpoint reviews the actual development of MSCs, MSCs-CM and MSCs-exosomes for treating patients with AD.