Dynamic interplay between IL-1 and WNT pathways in regulating dermal adipocyte lineage cells during skin development and wound regeneration.

Dermal adipocyte lineage cells are highly plastic and can undergo reversible differentiation and dedifferentiation in response to various stimuli. Using single-cell RNA sequencing of developing or wounded mouse skin, we classify dermal fibroblasts (dFBs) into distinct non-adipogenic and adipogenic cell states. Cell differentiation trajectory analyses identify IL-1-NF-κB and WNT-ß-catenin as top signaling pathways that positively and negatively associate with adipogenesis, respectively. Upon wounding, activation of adipocyte progenitors and wound-induced adipogenesis are mediated in part by neutrophils through the IL-1R-NF-κB-CREB signaling axis. In contrast, WNT activation, by WNT ligand and/or ablation of Gsk3, inhibits the adipogenic potential of dFBs but promotes lipolysis and dedifferentiation of mature adipocytes, contributing to myofibroblast formation. Finally, sustained WNT activation and inhibition of adipogenesis is seen in human keloids. These data reveal molecular mechanisms underlying the plasticity of dermal adipocyte lineage cells, defining potential therapeutic targets for defective wound healing and scar formation.

Modulation of Skin Inflammatory Responses by Aluminum Adjuvant.

Aluminum salt (AS), one of the most commonly used vaccine adjuvants, has immuno-modulatory activity, but how the administration of AS alone may impact the activation of the skin immune system under inflammatory conditions has not been investigated. Here, we studied the therapeutic effect of AS injection on two distinct skin inflammatory mouse models: an imiquimod (IMQ)-induced psoriasis-like model and an MC903 (calcipotriol)-induced atopic dermatitis-like model. We found that injection of a high dose of AS not only suppressed the IMQ-mediated development of T-helper 1 (Th1) and T-helper 17 (Th17) immune responses but also inhibited the IMQ-mediated recruitment and/or activation of neutrophils and macrophages. In contrast, AS injection enhanced MC903-mediated development of the T-helper 2 (Th2) immune response and neutrophil recruitment. Using an in vitro approach, we found that AS treatment inhibited Th1 but promoted Th2 polarization of primary lymphocytes, and inhibited activation of peritoneal macrophages but not bone marrow derived neutrophils. Together, our results suggest that the injection of a high dose of AS may inhibit Th1 and Th17 immune response-driven skin inflammation but promote type 2 immune response-driven skin inflammation. These results may provide a better understanding of how vaccination with an aluminum adjuvant alters the skin immune response to external insults.

Dermal extracellular matrix molecules in skin development, homeostasis, wound regeneration and diseases.

The extracellular matrix (ECM) is a dynamic structure that surrounds and anchors cellular components in tissues. In addition to functioning as a structural scaffold for cellular components, ECMs also regulate diverse biological functions, including cell adhesion, proliferation, differentiation, migration, cell-cell interactions, and intracellular signaling events. Dermal fibroblasts (dFBs), the major cellular source of skin ECM, develop from a common embryonic precursor to the highly heterogeneous subpopulations during development and adulthood. Upon injury, dFBs migrate into wound granulation tissue and transdifferentiate into myofibroblasts, which play a critical role in wound contraction and dermal ECM regeneration and deposition. In this review, we describe the plasticity of dFBs during development and wound healing and how various dFB-derived ECM molecules, including collagen, proteoglycans, glycosaminoglycans, fibrillins and matricellular proteins are expressed and regulated, and in turn how these ECM molecules play a role in regulating the function of dFBs and immune cells. Finally, we describe how dysregulation of ECM matrix is associated the pathogenesis of wound healing related skin diseases, including chronic wounds and keloid.

Injectable calcium phosphate ceramics prevent osteoclastic differentiation and osteoporotic bone loss: Potential applications for regional osteolysis.

Calcium phosphates (CaPs) in the form of blocks are typically not satisfied for administration to osteoporotic patients because of their rapid resorption rate in vivo. However, injectable CaP powders have not been investigated for their potential in osteoporotic hosts. Herein, CaPs in the form of nanoparticles was reported can inhibit RANKL-stimulated osteoclastic differentiation (OC) and bone resorption, as evidenced by suppressed TRAP-positive cells, disintegrated F-actin rings and downregulated expression of markers for OC. CaP powders also significantly inhibited nuclear factor-κB (NF-κB) and nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) activation. Furthermore, injectable CaPs reversed bone loss in a mouse model induced by lipopolysaccharide (LPS) and promoted osteoblastic formation in the absent of pro-osteogenic agents. Therefore, injectable CaPs, especially biphasic calcium phosphate (BCP), could be developed as novel agents for the therapy of osteolysis-related diseases caused by inflammation.

Biomimetic Poly(Poly(ε-caprolactone)-Polytetrahydrofuran urethane) Based Nanofibers Enhanced Chondrogenic Differentiation and Cartilage Regeneration.

Scaffolds for stem cell-based therapy of cartilage defect require bioactivity and stiffness mimicking to the native cartilage matrix. In this study, we fabricated electrospun nanofibers composited of cartilage matrix components (collagen or chondroitin sulfate) and poly(ε-caprolactone)-polytetrahydrofuran (PCL-PTHF). PCL-PTHF with rat tail derived collagen was named PR and PCL-PTHF with chondroitin sulfate (PS) termed PS, which have a modulus of 7.5 MPa and 3.6 MPa, respectively, within the range of cartilage matrix. Their chondrogenic potential for guiding chondrogenic differentiation and promoting cartilage regeneration were investigated based upon mesenchymal stem cells (MSCs). Results showed that both PR and PS nanofibers have the ability to induce chondrogenesis of MSCs and accelerate the regeneration of injured cartilage surface, probably via the suppression of Tumor necrosis factor (TNF) signaling pathway as evidenced by microarray profiles. Comparatively, PR showed better chondrogenic potential both in vitro and in vivo than that of PS, which may induce chondrogenesis through Hypoxia inducing factor-1 (HIF-1) signaling pathway. This study may provide reference for MSC based therapy of cartilage defects.

Pulsed Magnetic Field Stimuli Can Promote Chondrogenic Differentiation of Superparamagnetic Iron Oxide Nanoparticles-Labeled Mesenchymal Stem Cells in Rats.

Mesenchymal stem cells (MSCs) have potential uses for cartilage repair due to the potential of chondrogenic differentiation. However, developing effective approaches to regulate chondrogenesis in vivo remains a big challenging. To address the limitations, we propose the application of magnetic fields, which features excellent performance for tissue penetration, good biocompatibility even at high magnetic strength, and wireless remote control. To test this concept, a pulsed magnetic field (PMF) was used to enhance the chondrogenesis of SPIO-labeled MSCs in a rat model of cartilage defects. The SPIO labeling not only efficiently strengthens the responsiveness of MSCs to the externally applied PMF but also enables in vivo non-invasive monitoring of MSCs with magnetic resonance imaging (MRI). Importantly, biochemical and gene expression analysis reveal the upregulation of certain cartilage biomarkers (i.e., SOX9 and COL2A1), showing that the PMF improves the chondrogenesis of MSCs via activation of the TGF-ß/SMAD signaling pathways. These results indicate a promising scheme for stem cell-based cartilage repair.

Mechanically cartilage-mimicking poly(PCL-PTHF urethane)/collagen nanofibers induce chondrogenesis by blocking NF-kappa B signaling pathway.

Cartilage cannot self-repair and thus regeneration is a promising approach to its repair. Here we developed new electrospun nanofibers, made of poly (ε-caprolactone)/polytetrahydrofuran (PCL-PTHF urethane) and collagen I from calf skin (termed PC), to trigger the chondrogenic differentiation of mesenchymal stem cells (MSCs) and the cartilage regeneration in vivo. We found that the PC nanofibers had a modulus (4.3 Mpa) lower than the PCL-PTHF urethane nanofibers without collagen I from calf skin (termed P) (6.8 Mpa) although both values are within the range of the modulus of natural cartilage (1-10 MPa). Both P and PC nanofibers did not show obvious difference in the morphology and size. Surprisingly, in the absence of the additional chondrogenesis inducers, the softer PC nanofibers could induce the chondrogenic differentiation in vitro and cartilage regeneration in vivo more efficiently than the stiffer P nanofibers. Using mRNA-sequence analysis, we found that the PC nanofibers outperformed P nanofibers in inducing chondrogenesis by specifically blocking the NF-kappa B signaling pathway to suppress inflammation. Our work shows that the PC nanofibers can serve as building blocks of new scaffolds for cartilage regeneration and provides new insights on the effect of the mechanical properties of the nanofibers on the cartilage regeneration.