Stem cell fate is influenced by specialized microenvironments that remain poorly defined in mammals. To explore the possibility that haematopoietic stem cells derive regulatory information from bone, accounting for the localization of haematopoiesis in bone marrow, we assessed mice that were genetically altered to produce osteoblast-specific, activated PTH/PTHrP receptors (PPRs). Here we show that PPR-stimulated osteoblastic cells that are increased in number produce high levels of the Notch ligand jagged 1 and support an increase in the number of haematopoietic stem cells with evidence of Notch1 activation in vivo. Furthermore, ligand-dependent activation of PPR with parathyroid hormone (PTH) increased the number of osteoblasts in stromal cultures, and augmented ex vivo primitive haematopoietic cell growth that was abrogated by gamma-secretase inhibition of Notch activation. An increase in the number of stem cells was observed in wild-type animals after PTH injection, and survival after bone marrow transplantation was markedly improved. Therefore, osteoblastic cells are a regulatory component of the haematopoietic stem cell niche in vivo that influences stem cell function through Notch activation. Niche constituent cells or signalling pathways provide pharmacological targets with therapeutic potential for stem-cell-based therapies.

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Osteoblastic cells regulate the haematopoietic stem cell niche

Reactive oxygen species (ROS) are generated as by-products of cellular metabolism, primarily in the mitochondria. When cellular production of ROS overwhelms its antioxidant capacity, damage to cellular macromolecules such as lipids, protein, and DNA may ensue. Such a state of “oxidative stress” is thought to contribute to the pathogenesis of a number of human diseases including those of the lung. Recent studies have also implicated ROS that are generated by specialized plasma membrane oxidases in normal physiological signaling by growth factors and cytokines. In this review, we examine the evidence for ligand-induced generation of ROS, its cellular sources, and the signaling pathways that are activated. Emerging concepts on the mechanisms of signal transduction by ROS that involve alterations in cellular redox state and oxidative modifications of proteins are also discussed.

Reactive oxygen species in cell signaling

Cells prepare for S phase during the G1 phase of the cell cycle. Cell biological methods have provided knowledge of cycle kinetics and of substages of G1 that are determined by extracellular signals. Through the use of biochemical and molecular biological techniques to study effects of growth factors, oncogenes, and inhibitors, intracellular events during G1 that lead to DNA synthesis are rapidly being discovered. Many cells in vivo are in a quiescent state (G0), with unduplicated DNA. Cells can be activated to reenter the cycle during G1. Similarly, cells in culture can be shifted between G0 and G1. These switches in and out of G1 are the main determinants of post-embryonic cell proliferation rate and are defectively controlled in cancer cells.

https://science.sciencemag.org/content/sci/246/4930/603.full.pdf

G1 events and regulation of cell proliferation.

https://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1006&context=covid19

SARS-CoV-2

Activation of the Hedgehog (Hh) signalling pathway by sporadic mutations or in familial conditions such as Gorlin's syndrome is associated with tumorigenesis in skin, the cerebellum and skeletal muscle. Here we show that a wide range of digestive tract tumours, including most of those originating in the oesophagus, stomach, biliary tract and pancreas, but not in the colon, display increased Hh pathway activity, which is suppressible by cyclopamine, a Hh pathway antagonist. Cyclopamine also suppresses cell growth in vitro and causes durable regression of xenograft tumours in vivo. Unlike in Gorlin's syndrome tumours, pathway activity and cell growth in these digestive tract tumours are driven by endogenous expression of Hh ligands, as indicated by the presence of Sonic hedgehog and Indian hedgehog transcripts, by the pathway- and growth-inhibitory activity of a Hh-neutralizing antibody, and by the dramatic growth-stimulatory activity of exogenously added Hh ligand. Our results identify a group of common lethal malignancies in which Hh pathway activity, essential for tumour growth, is activated not by mutation but by ligand expression.

Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours

A review of chemistry and biological activity of genus Atalantia (Rutaceae).

Fabrication, characterization and in vivo assessment of cardiogel loaded chitosan patch for myocardial regeneration.

Emerging Trends in Mesenchymal Stem Cells Applications for Cardiac Regenerative Therapy: Current Status and Advances

Metal-free semi-aromatic polyester: A novel nanomaterial for potential clinical application

The present work deals with the development of smart nanogels with a coating of the lipid layer, which synergized the triggered delivery of the anticancer drug, cisplatin (CP). In the first step, the chemical initiation method carried out the grafting of polyitaconic acid (PIA) on Tragacanth gum (TG). Subsequently, this grafted TG matrix was used for the synthesis of nanoparticles. Nanoemulsion process was followed to prepare CP loaded grafted TG-Lecithin (nGTG-LC) nanogels using dioctyl sulfosuccinate (AOT), as the surfactant. These nanoparticles were characterized for size, morphology, elemental analysis, and crystallinity. The TEM images of GTG-LC nanogels with varying concentrations of CP demonstrated the irregular polygonal shape of the nanoparticles which is strongly influenced by the CP concentration. The smart nanogels exhibit a unique structure, nano-within-nano, the structure where nano-sized CP is encapsulated within the TG-LC nanogel. Grafted nanogels have a high carboxyl functionality and acquire pH-sensitive behavior leading to pH-responsive drug release behavior. These nanogel show required biocompatibility and offer interesting material for nanomedicines in chemotherapy. This article is protected by copyright. All rights reserved. 

Rama Shanker Verma

Papers

A review of chemistry and biological activity of genus Atalantia (Rutaceae).

Fabrication, characterization and in vivo assessment of cardiogel loaded chitosan patch for myocardial regeneration.

Emerging Trends in Mesenchymal Stem Cells Applications for Cardiac Regenerative Therapy: Current Status and Advances

Metal-free semi-aromatic polyester: A novel nanomaterial for potential clinical application

Designing of Smart Nanogels based on Tragacanth Gum for Cisplatin Delivery