The Transcriptome of Human Endometrial Mesenchymal Stem Cells Under TGFβR Inhibition Reveals Improved Potential for Cell-Based Therapies

Mesenchymal stem/stromal cells (MSCs) are multipotent cells with favorable properties for cell therapies and regenerative medicine. Human endometrium harbors a small population of perivascular, clonogenic MSCs (eMSCs) identified by the SUSD2 marker. As for other MSCs, eMSCs require extensive in vitro expansion to generate clinically relevant numbers of cells, resulting in spontaneous differentiation, replicative senescence and cell death, decreasing therapeutic potency. We previously demonstrated that A83-01, a TGF-β receptor inhibitor, maintained eMSC clonogenicity, promoted proliferation, prevented apoptosis and maintained MSC function in vitro. Here we compare the transcriptome of passaged eMSCs from six women cultured with and without A83-01 for 7 days. We identified 1206 differentially expressed genes (DEG) using a false discovery rate cut-off at 0.01 and fold change >2. Significant enrichment of genes involved in anti-inflammatory responses, angiogenesis, cell migration and proliferation, and collagen fibril and extracellular matrix organization were revealed. TGF-β, Wnt and Akt signaling pathways were decreased. Anti-fibrotic and anti-apoptotic genes were induced, and fibroblast proliferation and myofibroblast related genes were downregulated. We found increased MSC potency genes (TWIST1, TWIST2, JAG1, LIFR, and SLIT2) validating the enhanced potency of A83-01-treated eMSCs, and importantly no pluripotency gene expression. We also identified eMSCs’ potential for secreting exosomes, possibly explaining their paracrine properties. Angiogenic and cytokine protein arrays confirmed the angiogenic, anti-fibrotic and immunomodulatory phenotype of A83-01-treated eMSCs, and increased angiogenic activity was functionally demonstrated in vitro. eMSCs culture expanded with A83-01 have enhanced clinically relevant properties, suggesting their potential for cell-therapies and regenerative medicine applications

Nominalphrasen in literarischen Texten : Strukturtypen und Funktionen beim Figurenentwurf in Werken des 20. und 21. Jahrhunderts

Nominalphrasen und ihre Teile tragen wesentlich dazu bei, Wissen über literarische Figuren einzuführen und eingeführtes figurenbezogenes Wissen an relevanten Stellen zu aktualisieren. Das vorliegende Buch bewegt sich an der Schnittstelle von Grammatik und Textlinguistik: Anhand von ausgewählten Werken des 20. und 21. Jahrhunderts wird systematisch und detailliert dargestellt, welche Strukturtypen von Nominalphrasen eingesetzt werden, um bei der Figureneinführung bzw. beim Weiterreden über literarische Figuren bestimmte Dimensionen der Figurencharakterisierung anzusprechen. In einer Fallstudie wird darüber hinaus nach der Dynamik des Wissensaufbaus im Textstrom gefragt

Enhanced articular cartilage by human mesenchymal stem cells in enzymatically mediated transiently RGDS-functionalized collagen-mimetic hydrogels

Recapitulation of the articular cartilage microenvironment for regenerative medicine applications faces significant challenges due to the complex and dynamic biochemical and biomechanical nature of native tissue. Towards the goal of biomaterial designs that enable the temporal presentation of bioactive sequences, recombinant bacterial collagens such as Streptococcal collagen-like 2 (Scl2) proteins can be employed to incorporate multiple specific bioactive and biodegradable peptide motifs into a single construct. Here, we first modified the backbone of Scl2 with glycosaminoglycan-binding peptides and cross-linked the modified Scl2 into hydrogels via matrix metalloproteinase 7 (MMP7)-cleavable or non-cleavable scrambled peptides. The cross-linkers were further functionalized with a tethered RGDS peptide creating a system whereby the release from an MMP7-cleavable hydrogel could be compared to a system where release is not possible. The release of the RGDS peptide from the degradable hydrogels led to significantly enhanced expression of collagen type II (3.9-fold increase), aggrecan (7.6-fold increase), and SOX9 (5.2-fold increase) by human mesenchymal stem cells (hMSCs) undergoing chondrogenesis, as well as greater extracellular matrix accumulation compared to non-degradable hydrogels (collagen type II; 3.2-fold increase, aggrecan; 4-fold increase, SOX9; 2.8-fold increase). Hydrogels containing a low concentration of the RGDS peptide displayed significantly decreased collagen type I and X gene expression profiles, suggesting a major advantage over either hydrogels functionalized with a higher RGDS peptide concentration, or non-degradable hydrogels, in promoting an articular cartilage phenotype. These highly versatile Scl2 hydrogels can be further manipulated to improve specific elements of the chondrogenic response by hMSCs, through the introduction of additional bioactive and/or biodegradable motifs. As such, these hydrogels have the possibility to be used for other applications in tissue engineering. Statement of Significance Recapitulating aspects of the native tissue biochemical microenvironment faces significant challenges in regenerative medicine and tissue engineering due to the complex and dynamic nature of the tissue. The ability to take advantage of, mimic, and modulate cell-mediated processes within novel naturally-derived hydrogels is of great interest in the field of biomaterials to generate constructs that more closely resemble the biochemical microenvironment and functions of native biological tissues such as articular cartilage. Towards this goal, the temporal presentation of bioactive sequences such as RGDS on the chondrogenic differentiation of human mesenchymal stem cells is considered important as it has been shown to influence the chondrogenic phenotype. Here, a novel and versatile platform to recreate a high degree of biological complexity is proposed, which could also be applicable to other tissue engineering and regenerative medicine applications

Identification and characterization of human endometrial mesenchymal stem/stromal cells and their potential for cellular therapy

Human endometrium is a highly regenerative tissue, undergoing more than 400 cycles of proliferation, differentiation, and shedding during a woman’s reproductive life. Adult stem cells, including mesenchymal stem/stromal cells (MSCs), are likely responsible for the immense cellular turnover in human endometrium. The unique properties of MSCs, including high proliferative ability, self-renewal, differentiation to mesodermal lineages, secretion of angiogenic factors, and many other growth-promoting factors make them useful candidates for cellular therapy and tissue engineering. In this review, we summarize the identification and characterization of newly discovered MSCs from the human endometrium: their properties, the surface markers used for their prospective isolation, their perivascular location in the endometrium, and their potential application in cellular therapies. SIGNIFICANCE: The endometrium, or the lining of uterus, has recently been identified as a new and accessible source of mesenchymal stem cells, which can be obtained without anesthesia. Endometrial mesenchymal stem cells have comparable properties to bone marrow and adipose tissue mesenchymal stem cells. Endometrial mesenchymal stem cells are purified with known and novel perivascular surface markers and are currently under investigation for their potential use in cellular therapy for several clinical conditions with significant burden of disease

Immunobiology and Application of <i>Aloe vera</i>-Based Scaffolds in Tissue Engineering

Aloe vera (AV), a succulent plant belonging to the Liliaceae family, has been widely used for biomedical and pharmaceutical application. Its popularity stems from several of its bioactive components that have anti-oxidant, anti-microbial, anti-inflammatory and even immunomodulatory effects. Given such unique multi-modal biological impact, AV has been considered as a biomaterial for regenerative medicine and tissue engineering applications, where tissue repair and neo-angiogenesis are vital. This review outlines the growing scientific evidence that demonstrates the advantage of AV as tissue engineering scaffolds. We particularly highlight the recent advances in the application of AV-based scaffolds. From a tissue engineering perspective, it is pivotal that the implanted scaffolds strike an appropriate foreign body response to be well-accepted in the body without complications. Herein, we highlight the key cellular processes that regulate the foreign body response to implanted scaffolds and underline the immunomodulatory effects incurred by AV on the innate and adaptive system. Given that AV has several beneficial components, we discuss the importance of delving deeper into uncovering its action mechanism and thereby improving material design strategies for better tissue engineering constructs for biomedical applications