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The epidermis of the skin provides a barrier between the organism and the external environment. It is constantly subjected to physical and chemical insults, and thus susceptible to wounding and to neoplastic transformation. Long-lasting epigenetic modifications in epidermal stem cells are now shown to link responses to skin injuries with cell priming for carcinoma development, through regulation of histone H2A ubiquitylation. [ABSTRACT FROM AUTHOR]

Stem cell therapy has emerged as a promising avenue for regenerative medicine, offering the potential to treat a wide range of debilitating diseases and injuries. Among the various types of stem cells, mesenchymal stem cells (MSCs) have garnered significant attention due to their unique properties and therapeutic potential. In recent years, researchers have been exploring novel approaches to enhance the effectiveness of MSC-based therapies. One such approach that has gained traction is the priming of MSCs with molecular hydrogen (H2). This article delves into the fascinating world of mesenchymal stem cell priming with molecular hydrogen and the potential benefits it holds for regenerative medicine. [ABSTRACT FROM AUTHOR]

Stem cell therapy has emerged as a promising avenue for regenerative medicine, offering the potential to treat a wide range of debilitating diseases and injuries. Among the various types of stem cells, mesenchymal stem cells (MSCs) have garnered significant attention due to their unique properties and therapeutic potential. In recent years, researchers have been exploring novel approaches to enhance the effectiveness of MSC-based therapies. One such approach that has gained traction is the priming of MSCs with molecular hydrogen (H2). This article delves into the fascinating world of mesenchymal stem cell priming with molecular hydrogen and the potential benefits it holds for regenerative medicine.

Background and Aims: Hypoxia in the intestinal epithelium can be caused by acute ischemic events or chronic inflammation in which immune cell infiltration produces inflammatory hypoxia starving the mucosa of oxygen. The epithelium has the capacity to regenerate after some ischemic and inflammatory conditions suggesting that intestinal stem cells (ISCs) are highly tolerant to acute and chronic hypoxia; however, the impact of hypoxia on human ISC (hISC) function has not been reported. Here we present a new microphysiological system (MPS) to investigate how hypoxia affects hISCs from healthy donors and test the hypothesis that prolonged hypoxia modulates how hISCs respond to inflammation-associated interleukins (ILs). Methods: hISCs were exposed to

Temporomandibular joint osteoarthritis (TMJOA) is a degenerative disorder affecting the temporomandibular joint (TMJ), marked by persistent inflammation and structural damage to the joint. Only symptomatic treatment is available for managing TMJOA. Human umbilical cord mesenchymal stem cells (hUC-MSCs) show potential for treating TMJOA via their immune-modulating actions in the disease area. In addition, stimulation of inflammatory cytokines such as interferon-gamma in hUC-MSCs improves the therapeutic activity of naïve stem cells. Emerging evidence indicates that macrophages play significant roles in regulating joint inflammation through diverse secreted mediators in the pathogenesis of TMJOA. This study was conducted to evaluate the effects of inflammatory cytokine-stimulated hUC-MSCs in repairing TMJOA-induced cartilage lesions and the role of macrophages in the disease. Our in vitro data showed that stimulated hUC-MSCs induce M2 polarization of macrophages and enhance the expression of anti-inflammatory molecules. These effects were subsequently validated in vivo . In a rat model of TMJOA, stimulated hUC-MSCs ameliorated inflammation and increased M2 macrophages ratio. Our results indicate that hUC-MSCs stimulated by inflammatory cytokines modulate the activation of M2 macrophages, thereby shifting the local osteoarthritis microenvironment toward a prochondrogenic state and facilitating cartilage repair in inflammatory conditions. Stimulating hUC-MSCs with inflammatory cytokines could potentially offer an effective therapeutic approach for TMJOA, with macrophages playing a pivotal role in immune modulation.

A combinatorial approach integrating stem cells and capable of exploiting available cues is likely needed to regenerate lost neural tissues and ultimately restore neurologic functions. This study investigates the effects of the subcutaneous maturation of adult-derived neural stem cell (aNSCs) seeded into biomaterial constructs on aNSC differentiation and ultimate regional neuronal identity as a first step toward a future spinal cord injury treatment. To achieve this, we encapsulated rat aNSCs in chitosan-based hydrogels functionalized with immobilized azide-tagged interferon-γ inside a chitosan conduit. Then, we implanted these constructs in the subcutaneous tissues in the backs of rats in the cervical, thoracic, and lumbar regions for 4, 6, and 8 weeks. After harvesting the scaffolds, we analyzed cell differentiation qualitatively using immunohistochemical analysis and quantitatively using RT-qPCR. Results revealed that the hydrogels supported aNSC survival and differentiation up to 4 weeks in the subcutaneous environment as marked by the expression of several neurogenesis markers. Most interesting, the aNSCs expressed region-specific Hox genes corresponding to their region of implantation. This study lays the groundwork for further translational work to recapitulate the potentially undiscovered patterning cues in the subcutaneous tissue and provide support for the conceptual premise that our bioengineering approach can form caudalized region-specific neuroepithelium.

Background and Aims: Hypoxia in the intestinal epithelium can be caused by acute ischemic events or chronic inflammation in which immune cell infiltration produces inflammatory hypoxia starving the mucosa of oxygen. The epithelium has the capacity to regenerate after some ischemic and inflammatory conditions suggesting that intestinal stem cells (ISCs) are highly tolerant to acute and chronic hypoxia; however, the impact of hypoxia on human ISC (hISC) function has not been reported. Here we present a new microphysiological system (MPS) to investigate how hypoxia affects hISCs from healthy donors and test the hypothesis that prolonged hypoxia modulates how hISCs respond to inflammation-associated interleukins (ILs)., Methods: hISCs were exposed to <1.0% oxygen in the MPS for 6, 24, 48, and 72 hours. Viability, hypoxia-inducible factor 1a (HIF1a) response, transcriptomics, cell cycle dynamics, and response to cytokines were evaluated in hISCs under hypoxia. HIF stabilizers and inhibitors were screened to evaluate HIF-dependent responses., Results: The MPS enables precise, real-time control and monitoring of oxygen levels at the cell surface. Under hypoxia, hISCs maintain viability until 72 hours and exhibit peak HIF1a at 24 hours. hISC activity was reduced at 24 hours but recovered at 48 hours. Hypoxia induced increases in the proportion of hISCs in G1 and expression changes in 16 IL receptors. Prolyl hydroxylase inhibition failed to reproduce hypoxia-dependent IL-receptor expression patterns. hISC activity increased when treated IL1β, IL2, IL4, IL6, IL10, IL13, and IL25 and rescued hISC activity caused by 24 hours of hypoxia., Conclusions: Hypoxia pushes hISCs into a dormant but reversible proliferative state and primes hISCs to respond to a subset of ILs that preserves hISC activity. These findings have important implications for understanding intestinal epithelial regeneration mechanisms caused by inflammatory hypoxia., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Various stem cells have been found to be dependent on mitochondrial energetics. The role of mitochondria in regulating the self-renewal of normal stem cells and stem-like tumor initiating cells (TICs) is increasingly being appreciated. We proposed that TIC populations have a sub population of cells that are "primed" by mitochondria for self-renewal. Using ovarian cancer model, we have developed a protocol to identify and isolate these "primed" cells using Fluorescence-Assisted Cell Sorting (FACS). We combined live cell stains for a functional marker of TICs and for mitochondrial transmembrane potential to enrich TICs with higher mitochondrial potential that form in vitro spheroids 10-fold more than the other TICs with lower mitochondrial potential. This protocol can be directly used or modified to be used in various cell types. Thus, this protocol is anticipated to be invaluable for the basic understanding of mitochondrial and energetic heterogeneity within stem cell population, and may also prove valuable in translational studies in regenerative medicine and cancer biology., Competing Interests: Competing interestsThe authors have no competing interests., (Copyright © 2021 The Authors; exclusive licensee Bio-protocol LLC.)

A combinatorial approach integrating stem cells and capable of exploiting available cues is likely needed to regenerate lost neural tissues and ultimately restore neurologic functions. This study investigates the effects of the subcutaneous maturation of adult-derived neural stem cell (aNSCs) seeded into biomaterial constructs on aNSC differentiation and ultimate regional neuronal identity as a first step toward a future spinal cord injury treatment. To achieve this, we encapsulated rat aNSCs in chitosan-based hydrogels functionalized with immobilized azide-tagged interferon-γ inside a chitosan conduit. Then, we implanted these constructs in the subcutaneous tissues in the backs of rats in the cervical, thoracic, and lumbar regions for 4, 6, and 8 weeks. After harvesting the scaffolds, we analyzed cell differentiation qualitatively using immunohistochemical analysis and quantitatively using RT-qPCR. Results revealed that the hydrogels supported aNSC survival and differentiation up to 4 weeks in the subcutaneous environment as marked by the expression of several neurogenesis markers. Most interesting, the aNSCs expressed region-specific Hox genes corresponding to their region of implantation. This study lays the groundwork for further translational work to recapitulate the potentially undiscovered patterning cues in the subcutaneous tissue and provide support for the conceptual premise that our bioengineering approach can form caudalized region-specific neuroepithelium. [ABSTRACT FROM AUTHOR]

The immunoregulatory function of T regulatory cells (Tregs) is impaired in multiple sclerosis (MS). Recent studies have shown that umbilical cord-derived mesenchymal stem cells (UC-MSCs) exert regulatory effect on the functions of immune cells. Thus, we investigated whether UC-MSCs could improve the impaired function of Tregs from MS patients. Co-cultures of UC-MSCs with PBMCs of MS patients were performed for 3 days. Flow cytometry was used to determine the frequency of Tregs. A cell proliferation assay was used to evaluate the suppressive capacity of Tregs. ELISA was conducted for cytokine analysis in the co-cultures. Our results showed that UC-MSCs significantly increased the frequency of CD4+CD25+CD127low/- Tregs in resting CD4+ T cells (p<0.01) from MS, accompanied by the significantly augmented production of cytokine prostaglandin E2, transforming growth factor (-β1, and interleukin-10, along with a reduced interferon-γ production in these co-cultures (p<0.05 - 0.01). More importantly, UC-MSC-primed Tregs of MS patients significantly inhibited the proliferation of PHA-stimulated autologous and allogeneic CD4+CD25- T effector cells (Teffs) from MS patients and healthy individuals compared to non-UC-MSC-primed (naïve) Tregs from the same MS patients (p<0.01). Furthermore, no remarkable differences in suppressing the proliferation of PHA-stimulated CD4+CD25- Teffs was observed in UC-MSC-primed Tregs from MS patients and naïve Tregs from healthy subjects. The impaired suppressive function of Tregs from MS can be completely reversed in a co-culture by UC-MSC modulation. This report is the first to demonstrate that functional defects of Tregs in MS can be repaired in vitro using a simple UC-MSC priming approach.