Immunomodulatory properties of dental tissue-derived mesenchymal stem cells: Implication in disease and tissue regeneration.
Andrukhov Oleh,Behm Christian,Blufstein Alice,Rausch-Fan Xiaohui
World journal of stem cells
Mesenchymal stem cells (MSCs) are considered as an attractive tool for tissue regeneration and possess a strong immunomodulatory ability. Dental tissue-derived MSCs can be isolated from different sources, such as the dental pulp, periodontal ligament, deciduous teeth, apical papilla, dental follicles and gingiva. According to numerous studies, the effect of dental MSCs on immune cells might depend on several factors, such as the experimental setting, MSC tissue source and type of immune cell preparation. Most studies have shown that the immunomodulatory activity of dental MSCs is strongly upregulated by activated immune cells. MSCs exert mostly immunosuppressive effects, leading to the dampening of immune cell activation. Thus, the reciprocal interaction between dental MSCs and immune cells represents an elegant mechanism that potentially contributes to tissue homeostasis and inflammatory disease progression. Although the immunomodulatory potential of dental MSCs has been extensively investigated , its role remains obscure. A few studies have reported that the MSCs isolated from inflamed dental tissues have a compromised immunomodulatory ability. Moreover, the expression of some immunomodulatory proteins is enhanced in periodontal disease and even shows some correlation with disease severity. MSC-based immunomodulation may play an essential role in the regeneration of different dental tissues. Therefore, immunomodulation-based strategies may be a very promising tool in regenerative dentistry.
10.4252/wjsc.v11.i9.604
Macrophage response to hydrophilic biomaterials regulates MSC recruitment and T-helper cell populations.
Hotchkiss Kelly M,Clark Nicholas M,Olivares-Navarrete Rene
Biomaterials
Successful biomaterial implantation can be achieved by controlling the activation of the immune system. The innate immune system is typically the focus on synthetic material compatibility, but this study shows an effect of surface properties in the innate as well as the adaptive systems. These studies look at how macrophages respond to the implanted materials by releasing factors to regulate the microenvironment and recruit additional cells. Our research demonstrates how macrophage response to material surface properties can create changes in the adaptive immune response by altering T-helper cell populations and stem cell recruitment. Titanium (Ti) implants of varying wettability (rough, and rough-hydrophilic) were placed in the femur of 10-week-old male C57Bl/6, or macrophage ablated clodronate liposome injected and transgenic MaFIA (C57BL/6-Tg(Csf1r-EGFP-NGFR/FKBP1A/TNFRSF6)2Bck/J) mice. The microenvironment surrounding Ti implants was assessed using custom PCR arrays at 3 and 7 days following implantation. Changes in specific T-helper, macrophage and stem cell populations were evaluated locally at the implant surface and systemically in the contralateral leg bone marrow and spleen by flow cytometry at 1, 3 and 7 days. Macrophage importance in T-helper and stem cell population changes with metallic surfaces was examined in both in vitro and in vivo with macrophage ablation models. We demonstrate that surface modifications applied to titanium implants to increase surface roughness and wettability can polarize the adaptive immune response towards a Th2, pro-wound healing phenotype, leading to faster resolution of inflammation and increased stem cell recruitment around rough hydrophilic implants with macrophages present.
10.1016/j.biomaterials.2018.08.029
Electrical stimuli to increase cell proliferation on carbon nanotubes/mesoporous silica composites for drug delivery.
Vila M,Cicuéndez M,Sánchez-Marcos J,Fal-Miyar V,Manzano M,Prieto C,Vallet-Regi M
Journal of biomedical materials research. Part A
The development of smart materials as bone implants is nowadays a challenging task to optimize their fast osteointegration. Nevertheless, no attempts have been done in joining the possibility of using electrical stimulation and drug delivery together in a material intended for bone tissue engineering. Moreover, the use of this synergy to induce bone healing is still limited until novel drug reservoirs material formulations allow an efficient applicability of the electrical stimuli. Herein, we present the biological response of osteoblasts cells, cultured over carbon nanotubes-mesoporous silica composites while exposed to external electrical stimulus. Moreover, its ability to function as drug delivery systems is also demonstrated. Bone cell metabolism was stimulated and mitochondrial activity was increased up to seven times in the presence of these composites under electrical stimulus, suggesting their potential application in bone regeneration processes.
10.1002/jbm.a.34325
Role of molybdenum in material immunomodulation and periodontal wound healing: Targeting immunometabolism and mitochondrial function for macrophage modulation.
Biomaterials
Recently, strategies that can target the underlying mechanisms of phenotype change to modulate the macrophage immune response from the standpoint of biological science have attracted increasing attention in the field of biomaterials. In this study, we printed a molybdenum-containing bioactive glass ceramic (Mo-BGC) scaffold as an immunomodulatory material. In a clinically relevant critical-size periodontal defect model, the defect-matched scaffold featured robust immunomodulatory activity, enabling long-term stable macrophage modulation and leading to enhanced regeneration of multiple periodontal tissues in canines. Further studies demonstrated that the regeneration-enhancing function of Mo-BGC scaffold was macrophage-dependent by using canines with host macrophage depletion. To investigate the role of Mo in material immunomodulation, in vitro investigations were performed and revealed that Mo-BGC powder extract, similar to MoO-containing medium, induced M2 polarization by enhancing the mitochondrial function of macrophages and promoted a cell metabolic shift from glycolysis toward mitochondrial oxidative phosphorylation. Our findings demonstrate for the first time an immunomodulatory role of a Mo-containing material in the dynamic cascade of wound healing. By targeting the immunometabolism and mitochondrial function of macrophages, Mo-mediated immunomodulation provides new avenues for future material design in the field of tissue engineering and regenerative medicine.
10.1016/j.biomaterials.2022.121439
Biomimetic immunomodulation strategies for effective tissue repair and restoration.
Villarreal-Leal Ramiro Alejandro,Healey Gareth David,Corradetti Bruna
Advanced drug delivery reviews
Inflammation plays a central role in wound healing following injury or disease and is mediated by a precise cascade of cellular and molecular events. Unresolved inflammatory processes lead to chronic inflammation and fibrosis, which can result in prolonged wound healing lasting months or years that hampers tissue function. Therapeutic interventions mediated by immunomodulatory drugs, cells, or biomaterials, are therefore most effective during the inflammatory phase of wound healing when a pro-regenerative environment is essential. In this review, we discuss the advantages of exploiting knowledge of the native tissue microenvironment to develop therapeutics capable of modulating the immune response and promoting functional tissue repair. In particular, we provide examples of the most recent biomimetic platforms proposed to accomplish this goal, with an emphasis on those able to induce macrophage polarization towards a pro-regenerative phenotype.
10.1016/j.addr.2021.113913
Modulating macrophage responses to promote tissue regeneration by changing the formulation of bone extracellular matrix from filler particles to gel bioscaffolds.
Wu Rui-Xin,He Xiao-Tao,Zhu Jin-Hao,Yin Yuan,Li Xuan,Liu Xiaohua,Chen Fa-Ming
Materials science & engineering. C, Materials for biological applications
Extracellular matrices (ECMs) derived from native tissues/organs have been used as biomaterials for tissue engineering and regenerative medicine in a wide range of preclinical and clinical settings. The success or failure of these applications is largely contingent on the host responses to the matrices in vivo. Despite retaining their native structural and functional proteins, bone ECM-based transplants have been reported to evoke adverse immune responses in many cases; thus, optimizing the immunomodulatory properties of bone ECMs is critical for ensuring downstream regenerative outcomes. Using a simple digestion-neutralization protocol, we transformed the commonly used bone-derived filler particles into gel bioscaffolds. Instead of inducing macrophages toward proinflammatory (M1) polarization, as reported in the literature and confirmed in the present study for ECM particles, the ECM gels were found to be more likely to polarize macrophages toward regulatory/anti-inflammatory (M2) phenotypes, leading to enhanced tissue regeneration in a rat periodontal defect model. The present work demonstrates a simple, practical and economical strategy to modify the immunomodulatory properties of bone ECMs before their in vivo transplantation and hence has important implications that may facilitate the use of ECM-based bioscaffolds derived from diverse sources of tissues for regenerative purposes.
10.1016/j.msec.2019.03.107
3D printing of Mo-containing scaffolds with activated anabolic responses and bi-lineage bioactivities.
Theranostics
When osteochondral tissues suffer from focal or degenerative lesions caused by trauma or disorders, it is a tough challenge to regenerate them because of the limited self-healing capacity of articular cartilage. In this study, a series of Mo-doped bioactive glass ceramic (Mo-BGC) scaffolds were prepared and then systematically characterized. The released MoO ions from 7.5Mo-BGC scaffolds played a vital role in regenerating articular cartilage and subchondral bone synchronously. The Mo-BGC scaffolds were fabricated through employing both a sol-gel method and 3D printing technology. SEM, EDS, HRTEM, XRD, ICPAES and mechanical strength tests were respectively applied to analyze the physicochemical properties of Mo-BGC scaffolds. The proliferation and differentiation of rabbit chondrocytes (RCs) and human bone mesenchymal stem cells (HBMSCs) cultured with dilute solutions of 7.5Mo-BGC powder extract were investigated . The co-culture model was established to explore the possible mechanism of stimulatory effects of MoO ions on the RCs and HBMSCs The efficacy of regenerating articular cartilage and subchondral bone using 7.5Mo-BGC scaffolds was evaluated . The incorporation of Mo into BGC scaffolds effectively enhanced the compressive strength of scaffolds owing to the improved surface densification. The MoO ions released from the 7.5Mo-BGC powders remarkably promoted the proliferation and differentiation of both RCs and HBMSCs. The MoO ions in the co-culture system significantly stimulated the chondrogenic differentiation of RCs and meanwhile induced the chondrogenesis of HBMSCs. The chondrogenesis stimulated by MoO ions happened through two pathways: 1) MoO ions elicited anabolic responses through activating the HIF-1α signaling pathway; 2) MoO ions inhibited catabolic responses and protected cartilage matrix from degradation. The study showed that 7.5Mo-BGC scaffolds were able to significantly promote cartilage/bone regeneration when implanted into rabbit osteochondral defects for 8 and 12 weeks, displaying bi-lineage bioactivities. The 3D-printed Mo-BGC scaffolds with bi-lineage bioactivities and activated anabolic responses could offer an effective strategy for cartilage/bone interface regeneration.
10.7150/thno.27088
Building capacity for macrophage modulation and stem cell recruitment in high-stiffness hydrogels for complex periodontal regeneration: Experimental studies in vitro and in rats.
Acta biomaterialia
Recently, we found that although high-stiffness matrices stimulated osteogenic differentiation of bone marrow-derived stromal cells (BMSCs), the macrophages (Mφs) in high-stiffness transglutaminase crosslinked gelatins (TG-gels) tended to undergo M1 polarization and hence compromised cell osteogenesis. In this study, we hypothesized that the copresentation of interleukin (IL)-4 and stromal cell-derived factor (SDF)-1α in high-stiffness TG-gels may enhance periodontal regeneration by modulating Mφ polarization and promoting endogenous stem cell recruitment. We found that Mφs were more likely to polarize toward an immunomodulatory M2 state in the presence of IL-4 and hence positively influence the osteogenic differentiation of BMSCs when these cells coexisted in either indirect or direct co-culture systems. In cell migration assays, BMSCs exhibited an enhanced capability to move toward gels containing SDF-1α, and more cells could be recruited into the three-dimensional matrix of TG-gels. When TG-gels containing IL-4 and/or SDF-1α were used to repair periodontal defects, more new bone (MicroCT) was formed in animals that received the dual cytokine-loaded transplants at 4 weeks postsurgery. Mφs were recruited to all the transplanted gels, and after one week, more M1-phenotype cells were found in the groups without IL-4, while the presence of IL-4 was more likely to result in M2 polarization (immunofluorescence staining). When the tissue biopsies were histologically examined, the TG-gels containing both IL-4 and SDF-1α led to a generally satisfactory regeneration with respect to attachment recovery (epithelial and connective tissue) and hybrid tissue regeneration (bone, periodontal ligament and cementum). Our data suggest that the incorporation of IL-4 into high-stiffness TG-gels may promote the M2 polarization of Mφs and that SDF-1α can be applied to guide endogenous cell homing. Overall, building capacity for Mφ modulation and cell recruitment in high-stiffness hydrogels represents a simple and effective strategy that can support high levels of periodontal tissue regeneration. STATEMENT OF SIGNIFICANCE: The development of hydrogel-based regenerative therapies centered on the mobilization and stimulation of native cells for therapeutics opens a window toward realizing periodontal endogenous regeneration. In the present study, the parallel use of immunomodulatory and homing factors in high-stiffness hydrogel materials is shown to induce stem cell homing, modulate cell differentiation and indeed induce regrowth of the periodontium. We found that incorporation of interleukin (IL)-4 in high-stiffness TG-gels coaxed macrophages to polarize into M2 phenotypes, and stromal cell-derived factor (SDF)-1α could be applied to direct endogenous cell homing. Hence, we present for the first time a clinically relevant strategy based on macrophage modulation and host cell recruitment that can support high levels of periodontal tissue regeneration.
10.1016/j.actbio.2019.02.004