Preexisting tissue mechanical hypertension at adherens junctions disrupts apoptotic extrusion in epithelia.

Apical extrusion is a tissue-intrinsic process that allows epithelia to eliminate unfit or surplus cells. This is exemplified by the early extrusion of apoptotic cells, which is critical to maintain the epithelial barrier and prevent inflammation. Apoptotic extrusion is an active mechanical process, which involves mechanotransduction between apoptotic cells and their neighbors, as well as local changes in tissue mechanics. Here we report that the preexisting mechanical tension at adherens junctions (AJs) conditions the efficacy of apoptotic extrusion. Specifically, increasing baseline mechanical tension by overexpression of a phosphomimetic Myosin II regulatory light chain (MRLC) compromises apoptotic extrusion. This occurs when tension is increased in either the apoptotic cell or its surrounding epithelium. Further, we find that the proinflammatory cytokine, TNFα, stimulates Myosin II and increases baseline AJ tension to disrupt apical extrusion, causing apoptotic cells to be retained in monolayers. Importantly, reversal of mechanical tension with an inhibitory MRLC mutant or tropomyosin inhibitors is sufficient to restore apoptotic extrusion in TNFα-treated monolayers. Together, these findings demonstrate that baseline levels of tissue tension are important determinants of apoptotic extrusion, which can potentially be coopted by pathogenetic factors to disrupt the homeostatic response of epithelia to apoptosis.

Experimental and clinical data analysis for identification of COVID-19 resistant ACE2 mutations.

The high magnitude zoonotic event has caused by Severe Acute Respitarory Syndrome CoronaVirus-2 (SARS-CoV-2) is Coronavirus Disease-2019 (COVID-19) epidemics. This disease has high rate of spreading than mortality in humans. The human receptor, Angiotensin-Converting Enzyme 2 (ACE2), is the leading target site for viral Spike-protein (S-protein) that function as binding ligands and are responsible for their entry in humans. The patients infected with COVID-19 with comorbidities, particularly cancer patients, have a severe effect or high mortality rate because of the suppressed immune system. Nevertheless, there might be a chance wherein cancer patients cannot be infected with SARS-CoV-2 because of mutations in the ACE2, which may be resistant to the spillover between species. This study aimed to determine the mutations in the sequence of the human ACE2 protein and its dissociation with SARS-CoV-2 that might be rejecting viral transmission. The in silico approaches were performed to identify the impact of SARS-CoV-2 S-protein with ACE2 mutations, validated experimentally, occurred in the patient, and reported in cell lines. The identified changes significantly affect SARS-CoV-2 S-protein interaction with ACE2, demonstrating the reduction in the binding affinity compared to SARS-CoV. The data presented in this study suggest ACE2 mutants have a higher and lower affinity with SARS-Cov-2 S-protein to the wild-type human ACE2 receptor. This study would likely be used to report SARS-CoV-2 resistant ACE2 mutations and can be used to design active peptide development to inactivate the viral spread of SARS-CoV-2 in humans.

Hematopoietic Stem Cell Factors: Their Functional Role in Self-Renewal and Clinical Aspects.

Hematopoietic stem cells (HSCs) possess two important properties such as self-renewal and differentiation. These properties of HSCs are maintained through hematopoiesis. This process gives rise to two subpopulations, long-term and short-term HSCs, which have become a popular convention for treating various hematological disorders. The clinical application of HSCs is bone marrow transplant in patients with aplastic anemia, congenital neutropenia, sickle cell anemia, thalassemia, or replacement of damaged bone marrow in case of chemotherapy. The self-renewal attribute of HSCs ensures long-term hematopoiesis post-transplantation. However, HSCs need to be infused in large numbers to reach their target site and meet the demands since they lose their self-renewal capacity after a few passages. Therefore, a more in-depth understanding of ex vivo HSCs expansion needs to be developed to delineate ways to enhance the self-renewability of isolated HSCs. The multifaceted self-renewal process is regulated by factors, including transcription factors, miRNAs, and the bone marrow niche. A developed classical hierarchical model that outlines the hematopoiesis in a lineage-specific manner through in vivo fate mapping, barcoding, and determination of self-renewal regulatory factors are still to be explored in more detail. Thus, an in-depth study of the self-renewal property of HSCs is essentially required to be utilized for ex vivo expansion. This review primarily focuses on the Hematopoietic stem cell self-renewal pathway and evaluates the regulatory molecular factors involved in considering a targeted clinical approach in numerous malignancies and outlining gaps in the current knowledge.

Mesenchymal stem cell-based nanoparticles and scaffolds in regenerative medicine.

Mesenchymal stem cells (MSCs) are adult stem cells owing to their regenerative potential and multilineage potency. MSCs have wide-scale applications either in their native cellular form or in conjugation with specific biomaterials as nanocomposites. Majorly, these natural or synthetic biomaterials are being used in the form of metallic and non-metallic nanoparticles (NPs) to encapsulate MSCs within hydrogels like alginate or chitosan or drug cargo loading into MSCs. In contrast, nanofibers of polymer scaffolds such as polycaprolactone (PCL), poly-lactic-co-glycolic acid (PLGA), poly-L-lactic acid (PLLA), silk fibroin, collagen, chitosan, alginate, hyaluronic acid (HA), and cellulose are used to support or grow MSCs directly on it. These MSCs based nanotherapies have application in multiple domains of biomedicine including wound healing, bone and cartilage engineering, cardiac disorders, and neurological disorders. This review focused on current approaches of MSCs-based therapies and has been divided into two major sections. The first section elaborates on MSC-based nano-therapies and their plausible applications including exosome engineering and NPs encapsulation. The following section focuses on the various MSC-based scaffold approaches in tissue engineering. Conclusively, current review mainly discussed the MSC-based nanocomposite's current approaches their advantages and limitations for building effective regenerative medicines.

Cancer stem cells targets and combined therapies to prevent cancer recurrence.

Cancer stem cells (CSCs) control the dynamics of tumorigenesis by self-renewal ability and differentiation potential. These properties contribute towards tumor malignancy, metastasis, cellular heterogeneity, and immune escape, which are regulated by multiple signaling pathways. The CSCs are chemoresistant and cause cancer recurrence, generally recognized as a small side-population that eventually leads to tumor relapse. Despite many treatment options available, none can be considered entirely efficient due to a lack of specificity and dose limitation. This review primarily highlights the processes involved in CSCs development and maintenance. Secondly, the current effective therapies based on stem cells, cell-free therapies that involve exosomes and miRNAs, and photodynamic therapy have been discussed. Also, the inhibitors that specifically target various signaling pathways, which can be used in combination to control CSCs kinetics have been highlighted. Conclusively, this comprehensive review is a detailed study of recently developed novel treatment strategies that will facilitate in coming up with better-targeted approaches against CSCs.