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Wound healing is a complex process which depends on the presence of various types of cells, growth factors, cytokines and the elements of extracellular matrix. A wound is a portal of entry for numerous pathogens, therefore during the evolution wound healing process has formed very early, being critical for the survival of every individual. Stem cells, which give rise to their early descendants progenitor cells and subsequently differentiated cells, play a specific role in the process of wound healing. Among the most important cells which take part in wound healing the following cells need to be distinguished: epidermal stem cells, dermal precursor of fibroblasts, adipose-derived stem cells as well as bone marrow cells. The activity of these cells is strictly regulated by various growth factors, inter alia epidermal growth factor (EGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming growth factor (TGF), vascular endothelial growth factor (VEGF). Any disorders in functioning of stem cells and biological activity of growth factors may lead to the defects in wound healing, for instance delayed wound healing or creation of hypertrophic scars. Therefore, knowledge concerning the mechanisms of wound healing is extremely essential from clinical point of view. In this review the current state of the knowledge of the role of stem cells and growth factors in the process of wound healing has been presented. Moreover, some clinical aspects of wound healing as well as the possibility of the therapy based on stem cells and growth factors have included. [ABSTRACT FROM AUTHOR]

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Abstract: A recently discovered population of lymphocytes, called T regulatory cells (Tregs), is characterized by expression of transcription factor Forkhead box P3 (FoxP3). These cells have been successfully used as therapeutic treatments and prophylaxis for graft-versus-host disease (GVHD) and diabetes and might become an attractive alternative to traditional immunotherapy. Here we evaluated how the type of culture medium and the type of serum can influence yield and quality of Tregs after in vitro expansion. We compared Treg fold of expansion and their phenotypical characteristics including expression of FoxP3, CD25, CD127, CD62L and CD45RA in three commercially available culture media (RPMI 1640 (Cellgro; Manassas VA, USA), SCGM (Cellgenix; Freiburg, Germany), and X-VIVO 20 (Lonza; Walkersville, MD, USA)) with addition of human serum (HS, 10%) or fetal bovine serum (FBS, 10%). Among the tested media, X-VIVO 20 supplemented with HS produced the highest yield after 17days of in vitro expansion (a median of 86-fold expansion, range 30–1365) and highest level of FoxP3 expression (a median of 66.8% of positive cells, range 56–84.8%) in CD4+ CD25hiCD127lo/neg FACS sorted polyclonal Tregs. There was no difference in Tregs yield whether HS or FBS serum was used. In conclusion, the yield of the ex vivo expanded Tregs is related to the type of media applied. Supplementation of the culture with FBS or human serum is equally beneficial. [Copyright &y& Elsevier]

We focus here on the Hippo pathway in the hierarchical sensing and modulation of the mechanical state of the adult heart in health and disease. The Hippo pathway interrogates the micro-environment of cardiac myocytes providing surveillance of the mechanical state with engagement of signaling pathways critical to homeostasis of cardiac development, remodeling, and function and vulnerable to pathologies. Our discussion centers on Hippo signaling in the altered mechanical state instigated by variants of genes expressing mutant sarcomere proteins that trigger a progression to dilated cardiomyopathy (familial DCM). There is an unmet need for therapies in DCM. Recent progress in the discovery of small molecules that target Hippo signaling and are intended for use in cardiac disorders provides leads for modifying Hippo in DCM. As we emphasize, identifying useful targets in DCM requires in depth understanding of cell specific Hippo signaling in the cardiac micro-environment., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest.

In the heart, alternative splicing of the igf-I gene produces two isoforms: IGF-IEa and IGF-IEc, (Mechano-growth factor, MGF). The sequence divergence between their E-domain regions suggests differential isoform function. To define the biological actions of MGF's E-domain, we performed in silico analysis of the unique C-terminal sequence and identified a phosphorylation consensus site residing within a putative 14-3-3 binding motif. To test the functional significance of Ser 18 phosphorylation, phospho-mimetic (S/E 18 ) and phospho-null (S/A 18 ) peptides were delivered to mice at different doses for 2 weeks. Cardiovascular function was measured using echocardiography and a pressure-volume catheter. At the lowest (2.25 mg/kg/day) and highest (9 mg/kg/day) doses, the peptides produced a depression in systolic and diastolic parameters. However, at 4.5 mg/kg/day the peptides produced opposing effects on cardiac function. Fractional shortening analysis also showed a similar trend, but with no significant change in cardiac geometry. Microarray analysis discovered 21 genes (FDR p < 0.01), that were expressed accordant with the opposing effects on contractile function at 4.5 mg/kg/day, with the nuclear receptor subfamily 4 group A member 2 ( Nr4a2 ) identified as a potential target of peptide regulation. Testing the regulation of the Nr4a family, showed the E-domain peptides modulate Nr4a gene expression following membrane depolarization with KCl in vitro . To determine the potential role of 14-3-3 proteins, we examined 14-3-3 isoform expression and distribution. 14-3-3γ localized to the myofilaments in neonatal cardiac myocytes, the cardiac myocytes and myofilament extracts from the adult heart. Thermal shift analysis of recombinant 14-3-3γ protein showed the S/A 18 peptide destabilized 14-3-3γ folding. Also, the S/A 18 peptide significantly inhibited 14-3-3γ's ability to interact with myosin binding protein C (MYPC3) and phospholamban (PLN) in heart lysates from dobutamine injected mice. Conversely, the S/E 18 peptide showed no effect on 14-3-3γ stability, did not inhibit 14-3-3γ's interaction with PLN but did inhibit the interaction with MYPC3. Replacing the glutamic acid with a phosphate group on Ser 18 (pSer 18 ), significantly increased 14-3-3γ protein stability. We conclude that the state of Ser 18 phosphorylation within the 14-3-3 binding motif of MGF's E-domain, modulates protein-protein interactions within the 14-3-3γ interactome, which includes proteins involved in the regulation of contractile function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Solís, Thompson, Peña, McDermott-Roe, Langa, Warren, Chrzanowska, Wolska, Solaro, Pieter Detombe and Goldspink.)

We tested the hypothesis that isoform shifts in sarcomeres of the immature heart modify the effect of cardiac myosin-directed sarcomere inhibitors and activators. Omecamtiv mecarbil (OM) activates tension and is in clinical trials for the treatment of adult acute and chronic heart failure. Mavacamten (Mava) inhibits tension and is in clinical trials to relieve hypercontractility and outflow obstruction in advanced genetic hypertrophic cardiomyopathy (HCM), which is often linked to mutations in sarcomeric proteins. To address the effect of these agents in developing sarcomeres, we isolated heart fiber bundles, extracted membranes with Triton X-100, and measured tension developed over a range of Ca 2+ concentrations with and without OM or Mava treatment. We made measurements in fiber bundles from hearts of adult nontransgenic (NTG) controls expressing cardiac troponin I (cTnI), and from hearts of transgenic (TG-ssTnI) mice expressing the fetal/neonatal form, slow skeletal troponin I (ssTnI). We also compared fibers from 7- and 14-day-old NTG mice expressing ssTnI and cTnI. These studies were repeated with 7- and 14-day-old transgenic mice (TG-cTnT-R92Q) expressing a mutant form of cardiac troponin T (cTnT) linked to HCM. OM increased Ca 2+ -sensitivity and decreased cooperative activation in both ssTnI- and cTnI-regulated myofilaments with a similar effect: reducing submaximal tension in immature and mature myofilaments. Although Mava decreased tension similarly in cTnI- and ssTnI-regulated myofilaments controlled either by cTnT or cTnT-R92Q, its effect involved a depressed Ca 2+ -sensitivity in the mature cTnT-R92 myofilaments. Our data demonstrate an influence of myosin and thin-filament associated proteins on the actions of myosin-directed agents such as OM and Mava. SIGNIFICANCE STATEMENT: The effects of myosin-targeted activators and inhibitors on Ca 2+ -activated tension in developing cardiac sarcomeres presented here provide novel, ex vivo evidence as to their actions in early-stage cardiac disorders. These studies advance understanding of the molecular mechanisms of these agents, which are important in preclinical studies employing sarcomere Ca 2+ -response as a screening approach. The data also inform the use of commonly immature cardiac myocytes generated from human-inducible pluripotent stem cells in screening for sarcomere activators and inhibitors., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

Serum levels of thin filament proteins, cardiac troponin T (cTnT) and cardiac troponin I (cTnI) employing high sensitivity antibodies provide a state-of-the art determination of cardiac myocyte injury in COVID-19 patients. Although there is now sufficient evidence of the value of these determinations in patients infected with SARS-CoV-2, mechanisms of their release have not been considered in depth. We summarize the importance of these mechanisms with emphasis on their relation to prognosis, stratification, and treatment of COVID-19 patients. Apart from frank necrotic cell death, there are other mechanisms of myocyte injury leading to membrane fragility that provoke release of cTnT and cTnI. We discuss a rationale for understanding these mechanisms in COVID-19 patients with co-morbidities associated with myocyte injury such as heart failure, hypertension, arrythmias, diabetes, and inflammation. We describe how understanding these significant aspects of these mechanisms in the promotion of angiotensin signaling by SARS-CoV-2 can affect treatment options in the context of individualized therapies. Moreover, with likely omic data related to serum troponins and with the identification of elevations of serum troponins now more broadly detected employing high sensitivity antibodies, we think it is important to consider molecular mechanisms of elevations in serum troponin as an element in clinical decisions and as a critical aspect of development of new therapies.

SmartFlare™ RNA Detection Probes from Millipore is a novel technology to detect RNA in live cells based on the use of 12 nm gold nanoparticles coated with nucleotides. We proved that SmartFlares™ are internalized by human primary lymphocytes. However, fluorescence signals from target RNA detection can only be observed in the presence of Fetal Bovine Serum (FBS) in the medium, whereas it is not detectable without FBS or when medium is supplemented with human albumin. Image analysis of fluorescence generated from SmartFlare™ Uptake Control (gives constant signal regardless of contact with RNA) and RNA Specific Probes revealed further differences. In the presence of FBS, the fluorescence signal for both reagents was diffused within the cells, whereas in the absence of FBS, it was detected as single spots within the cells only when the Uptake Control was used. It is possible that FBS components are necessary for SmartFlare™ Probes to be released from cellular compartments into the cytoplasm where they can get into contact with target RNA. The exact mechanism of this phenomena should be further determined. However, for the first time, we present here that FBS in the cell culture medium is essential for RNA detection by SmartFlare™ technology in human lymphocytes., Competing Interests: Compliance with Ethical Standards: Conflict of Interest: The authors declare that they have no conflict of interest.