Stem Cell-based Tissue Repair Research Articles

Inhibited astrocytic differentiation in neural stem cell-laden 3D bioprinted conductive composite hydrogel scaffolds for repair of spinal cord injury

The emergence of three-dimensional (3D) bioprinting technology has attracted ever-increasing attention in engineered tissue fabrication for stem cell-based tissue repair. However, the in vivo performance of transplanted stem cells in the tissue engineering scaffolds is still a major concern for regenerative medicine researches. Especially for neural stem cell (NSC) transplantation, the uncontrollable differentiation of the NSCs in host often leads to a poor therapeutic effect in nerve tissue repair, such as spinal cord injury (SCI) repair. To address this issue, we have fabricated a conductive composite hydrogel (CCH) scaffold loading with NSCs by 3D bioprinting, for delivering the NSCs to injured spinal cord and repairing the propriospinal nerve circuit. In our strategy, a novel conductive polymer (PEDOT:CSMA,TA) was synthesized and introduced into a photocrosslinkable gelatin/polyethylene glycol physical-gel matrix, thereby forming a composite bioink with well shear-thinning and self-healing properties. The composite bioink we prepared was then printed into the NSC-laden CCH scaffold with high shape fidelity and similar physicochemical properties to native spinal cord tissues. The NSCs encapsulated in the bioprinted CCH scaffold extended their neurites to form superior physical contact with the neighboring cells as well as the electroconductive matrix, and maintained a predominant in vivo neuronal differentiation, accompanying with few astrocytic production in the lesion area after transplantation into the SCI sites. As a result, the removal of glial scar tissues and the regeneration of well-developed nerve fibres sequentially happened, which not only facilitated nerve tissue development, but also accelerated locomotor function recovery in the SCI rats. By exploring the application of conductive biomaterials in stem cell-based SCI therapy, this work represents a feasible, new approach to precisely construct tissue engineering scaffolds for stem cell-based therapy in traumatic SCI and other nervous system diseases.

Caveolin1: its roles in normal and cancer stem cells.

Stem cells are characterized by the capability of self-renewal and multi-differentiation. Normal stem cells, which are important for tissue repair and tissue regeneration, can be divided into embryonic stem cells (ESCs) and somatic stem cells (SSCs) depending on their origin. As a subpopulation of cells within cancer, cancer stem cells (CSCs) are at the root of therapeutic resistance. Tumor-initiating cells (TICs) are necessary for tumor initiation. Caveolin1 (Cav1), a membrane protein located at the caveolae, participates in cell lipid transport, cell migration, cell proliferation, and cell signal transduction. The purpose of this review was to explore the relationship between Cav1 and stem cells. In ESCs, Cav1 is beneficial for self-renewal, proliferation, and migration. In SSCs, Cav1 exhibits positive or/and negative effects on stem cell self-renewal, differentiation, proliferation, migration, and angiogenic capacity. Cav1 deficiency impairs normal stem cell-based tissue repair. In CSCs, Cav1 inhibits or/and promotes CSC self-renewal, differentiation, invasion, migration, tumorigenicity ability, and CSC formation. And suppressing Cav1 promotes chemo-sensitivity in CSCs and TICs. Cav1 shows dual roles in stem cell biology. Targeting the Cav1-stem cell axis would be a new way for tissue repair and cancer drug resistance.

Application of marine collagen for stem-cell-based therapy and tissue regeneration (Review).

Tissue engineering and regenerative medicine is becoming an important component in modern biological scientific research. Tissue engineering, a branch of regenerative medicine, is a field that is actively developing to meet the challenges presented in biomedical applications. This particularly applies to the research area of stem cells and biomaterials, due to both being pivotal determinants for the successful restoration or regeneration of damaged tissues and organs. Recently, the development of innovative marine collagen-based biomaterials has attracted attention due to the reported environmentally friendly properties, the lack of zoonotic disease transmission, biocompatibility, bioactivity, the lack of ethics-related concerns and cost-effectiveness for manufacturing. The present review aimed to summarize the potential application and function of marine collagen in stem cell research in a medical and clinical setting. In addition, the present review cited recent studies regarding the latest research advances into using marine collagen for cartilage, bone, periodontal and corneal regeneration. It also characterized the distinct advantages of using marine collagen for stem cell-based tissue repair and regeneration. In addition, the present review comprehensively discussed the most up to date information on stem cell biology, particularly the possibility of treating stem cells with marine collagen to maximize their multi-directional differentiation capability, which highlights the potential use of marine collagen in regenerative medicine. Furthermore, recent research progress on the potential immunomodulatory capacity of mesenchymal stem cells following treatment with marine collagen to improve the understanding of cell-matrix interactions was investigated. Finally, perspectives on the possible future research directions for the application of marine collagen in the area of regenerative medicine are provided.

The role of Interleukin 1 receptor antagonist in mesenchymal stem cell-based tissue repair and regeneration.

Interleukin (IL)-1 receptor antagonist (IL-1Ra), a naturally occurring antagonist of IL-1α/IL-1β signaling pathways, has been attributed to the immunosuppressive effects of mesenchymal stem cells (MSCs). MSCs, in IL-1Ra-dependent manner, suppressed production of IL-1β in dermal macrophages, induced their polarization in anti-inflammatory M2 phenotype, attenuated antigen-presenting properties of dendritic cells (DCs), and promoted expansion of immunosuppressive T regulatory cells in the skin, which resulted in enhanced repair of the nonhealing wounds. Reduced activation of inflammasome and suppressed production of IL-1β in macrophages were mainly responsible for beneficial effects of MSC-derived IL-1Ra in alleviation of acute lung injury, dry eye syndrome, and corneal injury. Through the production of IL-1Ra, MSCs reduced migration of DCs to the draining lymph nodes and attenuated generation of inflammatory Th1 and Th17 cells that resulted in alleviation of fulminant hepatitis and rheumatoid arthritis. MSCs, in IL-1Ra-dependent manner, reduced liver fibrosis by suppressing production of Type I collagen in hepatic stellate cells. IL-1Ra was, at least partially, responsible for enhanced proliferation of hepatocytes and chondrocytes in MSC-treated animals with partial hepatectomy and osteoarthritis. Despite of these beneficial effects, IL-1Ra-dependent inhibition of IL-1α/IL-1β-signaling significantly increased risk of infections. Therefore, future experimental and clinical studies should delineate potential side effects of MSC-derived IL-1Ra before IL-1Ra-overexpressing MSCs could be used as a potentially new therapeutic agent for the treatment of acute and chronic inflammatory diseases.

Covalent immobilization of MSC-affinity peptide on poly(L-lactide-co-ε-caprolactone) copolymer to enhance stem cell adhesion and retention for tissue engineering applications

Electrospun nanofibers mimicking the extracellular microenvironment have tremendous potential for tissue regeneration applications. However, a lack of bioactive functionalities limits the effective utilization of nanofibers fabricated from synthetic biodegradable polymers. The objective of this study was to conjugate mesenchymal stem cell affinity peptide (EPLQLKM, E7) with star-shaped poly(L-lactide-co-e-caprolactone) (PLCL) copolymer and to evaluate the potential of this modified polymer to enhance stem cell adhesion and proliferation in vitro. MSCadhesive peptide was covalently conjugated with the hydroxyl functionalities of the star-shaped PLCL copolymer and nanofibers were prepared by mixing appropriate proportions of linear PLCL and E7-conjugated star-shaped PLCL copolymers using electrospinning. Nuclear magnetic resonance and amino acid composition analysis revealed that E7 was successfully conjugated to PLCL copolymers. Nanofibers were smooth and homogenous as examined using scanning electron micrography. Nanofibrous meshes containing PLCL-E7 showed significantly higher cell viability and proliferation compared with the control group. In addition, cells spread well on meshes containing PLCL-E7 compared with the control group. The strategy adopted here may be very useful for designing stem cell adhesive polymeric biomaterials to enhance stem cell-based tissue repair. In addition, E7-immobilized PLCL copolymers can be fabricated into different shapes and structures as needed for various tissue engineering applications.

Conditioned medium from umbilical cord mesenchymal stem cells induces migration and angiogenesis.

Umbilical cord mesenchymal stem cells (UC-MSCs) have been suggested as a candidate for various clinical applications, however, major limitations include the lack of organ-specific accumulation and low survival rates of transplanted cells. In the present study, it was hypothesized that the paracrine effects of UC-MSCs may enhance stem cell-based tissue repair and regeneration by promoting the specific homing of stem/progenitor cells and the overall ability to drive them to the damaged area. UC-MSCs-derived conditioned medium (UC-CM) was analyzed using liquid chip and ELISA techniques. In vitro tube formation assays of human umbilical vein endothelial cells (HUVECs) and UC-MSCs were then performed to assess the angiogenic properties of UC-CM. Subsequently, UC-MSCs, HUVECs and fibroblasts were labeled with PKH26 for an in vivo cell migration assay. The expression levels of C-X-C chemokine receptor 4 (CXCR4), C-C chemokine receptor 2 (CCR2) and c-met were determined in the UC-MSCs, HUVECs and fibroblasts using reverse transcription-quantitative polymerase chain reaction and flow cytometry. UC-CM was incubated with or without antibodies, and the contribution of stromal cell-derived factor 1 (SDF-1), monocyte chemotactic protein 1 (MCP-1) and hepatocyte growth factor (HGF) on the migration of cells was investigated in vitro. The results demonstrated that UC-MSCs secreted different cytokines and chemokines, including increased quantities of SDF-1, MCP-1 and HGF, in addition to the angiogenic factors, vascular cell adhesion protein-1, interleukin-8, insulin-like growth factor-1 and vascular endothelial growth factor. The total lengths of the tubes were significantly increased in the UC-MSCs and HUVECs incubated in UC-CM compared with those incubated in Dulbecco’s modified Eagle’s medium. In vivo cell migration assays demonstrated that UC-CM was a chemotactic stimulus for the UC-MSCs and HUVECs. In vitro Matrigel migration and scratch healing assays demonstrated that UC-CM increased the migration of CXCR4-postive or/and CCR2-positive cells in a dose-dependent manner. In addition, different molecules were screened under antibody-based blocking migration conditions. The data revealed that the SDF-1/CXCR4 and MCP-1/CCR2 axes were involved in the chemoattractive activity of UC-CM and suggested that the effective paracrine factor of UC-CM is a large complex rather than a single factor. The results of the present study supported the hypothesis that UC-MSCs release soluble factors, which may extend the therapeutic applicability of stem cells.

An Open-Label Dose Escalation Study to Evaluate the Safety of Administration of Nonviral Stromal Cell-Derived Factor-1 Plasmid to Treat Symptomatic Ischemic Heart Failure

Preclinical studies indicate that adult stem cells induce tissue repair by activating endogenous stem cells through the stromal cell-derived factor-1:chemokine receptor type 4 axis. JVS-100 is a DNA plasmid encoding human stromal cell-derived factor-1. We tested in a phase 1, open-label, dose-escalation study with 12 months of follow-up in subjects with ischemic cardiomyopathy to see if JVS-100 improves clinical parameters. Seventeen subjects with ischemic cardiomyopathy, New York Heart Association class III heart failure, with an ejection fraction ≤40% on stable medical therapy, were enrolled to receive 5, 15, or 30 mg of JVS-100 via endomyocardial injection. The primary end points for safety and efficacy were at 1 and 4 months, respectively. The primary safety end point was a major adverse cardiac event. Efficacy end points were change in quality of life, New York Heart Association class, 6-minute walk distance, single photon emission computed tomography, N-terminal pro-brain natruretic peptide, and echocardiography at 4 and 12 months. The primary safety end point was met. At 4 months, all of the cohorts demonstrated improvements in 6-minute walk distance, quality of life, and New York Heart Association class. Subjects in the 15- and 30-mg dose groups exhibited improvements in 6-minute walk distance (15 mg: median [range]: 41 minutes [3-61 minutes]; 30 mg: 31 minutes [22-74 minutes]) and quality of life (15 mg: -16 points [+1 to -32 points]; 30 mg: -24 points [+17 to -38 points]) over baseline. At 12 months, improvements in symptoms were maintained. These data highlight the importance of defining the molecular mechanisms of stem cell-based tissue repair and suggest that overexpression of stromal cell-derived factor-1 via gene therapy is a strategy for improving heart failure symptoms in patients with ischemic cardiomyopathy.

Cell transplantation as an initiator of endogenous stem cell-based tissue repair

The aim of this review is to summarize recent findings of endogenous cell-based tissue repair triggered by a multitude of approaches, especially stem cell therapy. The emerging evidence has demonstrated that an important role of transplanted cells is to act as an initiator to trigger endogenous stem cell-mediated tissue repair after injury. Multiple approaches may orchestrate endogenous regeneration. The low efficacy of endogenous stem cells may be due to deficiency of cytokines to activate and induce endogenous stem cell homing, relatively insufficient endogenous stem cell pool, diseases or aging-related dysfunction of endogenous stem cells, and hostile microenvironments that limit the capacity of endogenous stem cells to repair damaged tissue. In certain situations, external stimulation and/or exogenous stem cells may be required to catalyze the repair. Endogenous stem cells are playing an important role in tissue repair. An important role of transplanted cells is to act as an initiator to trigger endogenous stem cell-based tissue repair.