• AKT/mTOR signaling pathway
• CD44s receptor
• Epithelial splicing regulatory protein 1
• Hyaluronan
• Stem cell senescence

• Humans
• Hyaluronic Acid/pharmacology
• Hyaluronic Acid/metabolism
• Cell Line, Tumor
• Proto-Oncogene Proteins c-akt
• Protein Isoforms/genetics
• Transcription Factors
• Stem Cells/metabolism
• TOR Serine-Threonine Kinases
• Hyaluronan Receptors/metabolism

• Adipogenesis
• Degenerative spondylolisthesis with spinal stenosis
• IL-19
• IL-1β
• IL-20
• Intervertebral disc
• Ligamentum flavum
• Osteogenesis

• Humans
• Adipogenesis
• Osteogenesis
• Interleukin-1beta/pharmacology
• Spinal Stenosis/pathology
• Ligamentum Flavum/pathology
• Spondylolisthesis/pathology
• Cell Differentiation
• Stem Cells

• Human amniotic epithelial cells
• Pro-proliferation
• TGF-β/BMP signaling pathway
• Hyaluronic acid

• Aging
• Cancer stem cells
• Geroprotection
• Regenerative medicine
• Side population
• Stem cell markers
• Stem cells
• VSELs
• Very small embryonic-like stem cells

• anti-aging
• hyaluronan
• lifespan
• mesenchymal stem cells
• quiescence

• Cellular proliferation
• Hyaluronan
• Mesenchymal stem cells
• Mitochondria
• Mitochondrial biogenesis

• Hyaluronan
• Neointima
• Smooth muscle cells
• Stem cells
• Vasculogenesis

Our previous results showed that hyaluronan (HA) preserved human placenta-derived mesenchymal stem cells (PDMSC) in a slow cell cycling mode similar to quiescence, the pristine state of stem cells in vivo, and HA was found to prevent murine adipose-derived mesenchymal stem cells from senescence. Here, stable isotope labeling by amino acid in cell culture (SILAC) proteomic profiling was used to evaluate the effects of HA on aging phenomenon in stem cells, comparing (1) old and young passage PDMSC cultured on normal tissue culture surface (TCS); (2) old passage on HA-coated surface (CHA) compared to TCS; (3) old and young passage on CHA. The results indicated that senescence-associated protein transgelin (TAGLN) was upregulated in old TCS. Protein CYR61, reportedly senescence-related, was downregulated in old CHA compared to old TCS. The SIRT1-interacting Nicotinamide phosphoribosyltransferase (NAMPT) increased by 2.23-fold in old CHA compared to old TCS, and is 0.48-fold lower in old TCS compared to young TCS. Results also indicated that components of endoplasmic reticulum associated degradation (ERAD) pathway were upregulated in old CHA compared to old TCS cells, potentially for overcoming stress to maintain cell function and suppress senescence. Our data points to pathways that may be targeted by HA to maintain stem cells youth.

• CD44
• adipose-derived stem cells
• glycosaminoglycans
• micropatterning

• Adipose Tissue/cytology
• Adult
• Animals
• Bone Marrow Cells/cytology
• Cattle
• Cell Adhesion/drug effects
• Cell Shape/drug effects
• Cells, Cultured
• Cytoskeleton/drug effects
• Cytoskeleton/metabolism
• Fibronectins/pharmacology
• Glycosaminoglycans/pharmacology
• Humans
• Hyaluronan Receptors/metabolism
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/drug effects
• Oxidation-Reduction/drug effects
• Proteins/pharmacology
• Serum Albumin, Bovine/pharmacology
• Surface Properties
• Young Adult

The glycosaminoglycan hyaluronan (HA), a major component of extracellular matrices, and cell surface receptors of HA have been proposed to have pivotal roles in cell proliferation, migration, and invasion, which are necessary for inflammation and cancer progression. CD44 and receptor for HA-mediated motility (RHAMM) are the two main HA-receptors whose biological functions in human and murine inflammations and tumor cells have been investigated comprehensively. HA was initially considered to be only an inert component of connective tissues, but is now known as a “dynamic” molecule with a constant turnover in many tissues through rapid metabolism that involves HA molecules of various sizes: high molecular weight HA (HMW HA), low molecular weight HA, and oligosaccharides. The intracellular signaling pathways initiated by HA interactions with CD44 and RHAMM that lead to inflammatory and tumorigenic responses are complex. Interestingly, these molecules have dual functions in inflammations and tumorigenesis. For example, the presence of CD44 is involved in initiation of arthritis, while the absence of CD44 by genetic deletion in an arthritis mouse model increases rather than decreases disease severity. Similar dual functions of CD44 exist in initiation and progression of cancer. RHAMM overexpression is most commonly linked to cancer progression, whereas loss of RHAMM is associated with malignant peripheral nerve sheath tumor growth. HA may similarly perform dual functions. An abundance of HMW HA can promote malignant cell proliferation and development of cancer, whereas antagonists to HA-CD44 signaling inhibit tumor cell growth in vitro and in vivo by interfering with HMW HA-CD44 interaction. This review describes the roles of HA interactions with CD44 and RHAMM in inflammatory responses and tumor development/progression, and how therapeutic strategies that block these key inflammatory/tumorigenic processes may be developed in rodent and human diseases.

• CD44
• RHAMM
• cancer
• hyaluronan
• inflammation

Scientific evidence suggests that stem cells possess the anti-aging ability to self-renew and maintain differentiation potentials, and quiescent state. The objective of this review is to discuss the micro-environment where stem cells reside in vivo, the secreted factors to which stem cells are exposed, the hypoxic environment, and intracellular factors including genome stability, mitochondria integrity, epigenetic regulators, calorie restrictions, nutrients, and vitamin D. Secreted tumor growth factor-β and fibroblast growth factor-2 are reported to play a role in stem cell quiescence. Extracellular matrices may interact with caveolin-1, the lipid raft on cell membrane to regulate quiescence. N-cadherin, the adhesive protein on niche cells provides support for stem cells. The hypoxic micro-environment turns on hypoxia-inducible factor-1 to prevent mesenchymal stem cells aging through p16 and p21 down-regulation. Mitochondria express glucosephosphate isomerase to undergo glycolysis and prevent cellular aging. Epigenetic regulators such as p300, protein inhibitors of activated Stats and H19 help maintain stem cell quiescence. In addition, calorie restriction may lead to secretion of paracrines cyclic ADP-ribose by intestinal niche cells, which help maintain intestinal stem cells. In conclusion, it is crucial to understand the anti-aging phenomena of stem cells at the molecular level so that the key to solving the aging mystery may be unlocked.

• Stem cells
• Anti-aging
• Quiescence
• Micro-environment

Evidence suggests that the human endometrium contains stem or progenitor cells that are responsible for its remarkable regenerative capability. A common property of somatic stem cells is their quiescent state. It remains unclear whether slow-cycling cells exist in the human endometrium. We hypothesized that the human endometrium contains a subset of slow-cycling cells with somatic stem cell properties. Here, we established an in vitro stem cell assay to isolate human endometrial-derived mesenchymal stem-like cells (eMSC).

Single-cell stromal cultures were initially labeled with fluorescent nanoparticles and a small population of fluorescent persistent cells (FPC) remained after culture of 21 days. Two populations of stromal cells, namely FPC and non-FPC were sorted.

Quantitative analysis of functional assays demonstrated that the FPC had higher colony forming ability, underwent more rounds of self-renewal and had greater enrichment of phenotypically defined prospective eMSC markers: CD146⁺/CD140b⁺ and W5C5⁺ than the non-FPC. They also differentiate into multiple mesenchymal lineages and the expression of lineage specific markers was lower than that of non-FPC. The FPC exhibit low proliferation activities. A proliferation dynamics study revealed that more FPC had a prolonged G₁ phase.

With this study we present an efficient method to label and isolate slow-proliferating cells obtained from human endometrial stromal cultures without genetic modifications. The FPC population could be easily maintained in vitro and are of interest for tissue-repair and engineering perspectives. In summary, nanoparticle labeling is a promising tool for the identification of putative somatic stem or progenitor cells when their surface markers are undefined.

Hyaluronan is a linear glycosaminoglycan that has received special attention in the last few decades due to its extraordinary physiological functions. This highly viscous polysaccharide is not only a lubricator, but also a significant regulator of cellular behaviors during embryogenesis, morphogenesis, migration, proliferation, and drug resistance in many cell types, including stem cells. Most hyaluronan functions require binding to its cellular receptors CD44, LYVE-1, HARE, layilin, and RHAMM. After binding, proteins are recruited and messages are sent to alter cellular activities. When low concentrations of hyaluronan are applied to stem cells, the proliferative activity is enhanced. However, at high concentrations, stem cells acquire a dormant state and induce a multidrug resistance phenotype. Due to the influence of hyaluronan on cells and tissue morphogenesis, with regards to cardiogenesis, chondrogenesis, osteogenesis, and neurogenesis, it is now been utilized as a biomaterial for tissue regeneration. This paper summarizes the most important and recent findings regarding the regulation of hyaluronan in cells.

• hyaluronic acid
• stem cells
• stem cells niche
• germinal cells
• sperm cells
• oocytes
• oxidative dna damage
• reactive oxidative species (ros)
• inflammation
• cell cycle
• apoptosis

• Animals
• Antioxidants/metabolism
• Cell Hypoxia/genetics
• Cell Hypoxia/physiology
• DNA Damage
• Female
• Genomic Instability/physiology
• Humans
• Hyaluronan Receptors/metabolism
• Hyaluronic Acid/metabolism
• Male
• Mutagens/metabolism
• Reactive Oxygen Species/metabolism
• Stem Cell Niche/genetics
• Stem Cell Niche/physiology
• Stem Cells/metabolism

• R01 CA028704 NCI NIH HHS
• R01 CA 28704 NCI NIH HHS

Evidence suggests that multiple tumors, including pancreatic adenocarcinoma, display heterogeneity in parameters that are critical for tumor formation, progression and metastasis. Understanding heterogeneity in solid tumors is increasingly providing a plethora of new diagnostic and therapeutic approaches. In this study, a particular focus was put on identifying a subpopulation of stem cell-like, slow cycling tumor cells in a pancreas adenocarcinoma cell lines. Using a label retention technique a subpopulation of slow cycling cells (DiI+/SCC) was identified and further evaluated in the BxPC-3 and Panc03.27 cell lines. These slowly cycling cells managed to retain the lipophilic labeling dye DiI, while the bulk of the cells (>94%) did not. The DiI+/SCC population, showed only a partial overlap with the CSC markers CD24⁺/CD44⁺, CD133⁺ and ALDH but they survived chemotherapeutic treatment, and were able to recreate the initial heterogeneous tumor cell population. DiI+/SCCs exhibited an increased invasive potential as compared with their non-label retaining, faster cycling cells (DiI−/FCC). They also had increased tumorigenic potential and morphological changes resembling cells that have undergone an epithelial to mesenchymal transition (EMT). Analysis of DiI+/SCC cells by real time PCR revealed a selective up-regulation of tell tale components of the Hedgehog/TGFβ pathways, as well as a down-regulation of EGFR, combined with a shift in crucial components implied in EMT. The presented findings offer an expanded mechanistic understanding that associates tumor initiating potential with cycling speed and EMT in pancreatic cancer cell lines.