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At least 127 records · Page 7

All sources NASA NTRS DOE OSTI

NASA NTRS2017

Osteogenic Transcription Regulated by Exaggerated Stretch Loading via Convergent Wnt Signaling

Cell and animal studies conducted onboard the International Space Station and formerly the Shuttle flights have provided data illuminating the deleterious biological response of bone to mechanical unloading. Down regulation of proliferative mechanisms within stem cell populations of the osteogenic niche is a suggested mechanism for loss of bone mass. However the intercellular communicative cues from osteoblasts and osteocytes in managing stem cell proliferation and osteogenic differentiation are largely unknown. In this investigation, MLO-Y4 osteocyte-like and MC3T3-E1 osteoblast-like cells, are co-culture under dynamic tensile conditions and evaluated for phenotypic expression of biochemical signaling proteins influential in driving stem cell differentiation. MLO-Y4 and MC3T3-E1 were co-cultured on polyethersulfone membrane with a 0.45m porosity to permit soluble factor transfer and direct cell-cell gap junction signaling. Cyclic tensile stimulation was applied for 48 h at a frequency of 0.1Hz and strain of 0.1. Total Live cell counts indicate mechanical activation of MC3T3-E1s inhibits proliferation while MLO-Y4s increase in number. However, the percent of live MLO-Y4s within the population is low (46.3 total count, *p0.05, n4) suggesting a potential apoptotic signaling cascade. Immunofluorescence demonstrated that stimulation of co-cultures elicits increased gap junction communication. Previously reported PCR evaluation of osteogenic markers further corroborate that the co-cultured populations communicative networks play a role in translating mechanical signals to molecular messaging. These findings suggest that an osteocyte-osteoblast signaling feedback mechanism may regulate mechanotransduction of an apoptotic cascade within osteocytes and transcription of cytokine signaling proteins responsible for stem cell niche recruitment much more directly than previously believed.

mechanical stimulation↗

NASA NTRS2016

Change in Mouse Bone Turnover in Response to Microgravity on RR-1

Mechanical unloading during spaceflight is known to adversely affect mammalian physiology. Our previous studies using the Animal Enclosure Module on short duration Shuttle missions enabled us to identify a deficit in stem cell based-tissue regeneration as being a significant concern for long-duration spaceflight. Specifically, we found that mechanical unloading in microgravity resulted in inhibition of differentiation of mesenchymal and hematopoietic stem cells in the bone marrow compartment. Also, we observed overexpression of a cell cycle arrest molecule, CDKN1ap21, in osteoprecursor cells on the bone surface, chondroprogenitors in the articular cartilage, and in myofibers attached to bone tissue. Specifically in bone tissue during both short (15-day) and long (30-day) microgravity experiments, we observed significant loss of bone tissue and structure in both the pelvis and the femur. After 15-days of microgravity on STS-131, pelvic ischium displayed a 6.23 decrease in bone fraction (p0.005) and 11.91 decrease in bone thickness (p0.002). Furthermore, during long-duration spaceflight we observed onset of an accelerated aging-like phenotype and osteoarthritic disease state indicating that stem cells within the bone tissue fail to repair and regenerate tissues in a normal manner, leading to drastic tissue alterations in response to microgravity. The Rodent Research Hardware System provides the capability to investigate these effects during long-duration experiments on the International Space Station. During the Rodent Research-1 mission 10 16-week-old female C57Bl6J mice were exposed to 37-days of microgravity. All flight animals were euthanized and frozen on orbit for future dissection. Ground (n10) and vivarium controls (n10) were housed and processed to match the flight animal timeline. During this study we collected pelvis, femur, and tibia from all animal groups to test the hypothesis that stem cell-based tissue regeneration is significantly altered after 37-days of spaceflight. To do this, we will analyze differences in bone morphometric parameters using MicroCT. The pelvis, femur, and tibia are key in supporting and distributing weight under normal conditions. Therefore, we expect to see altered remodeling in flight animals in response to microgravity with respect to ground controls. In combination with histomorphometry, these results will help elucidate the complex mechanisms underlying bone tissue maintenance and stem cell regeneration.

bone↗

DOE OSTI2021

Benefits and pathologies associated with the inflammatory response

Adult skeletal muscle regenerates completely after a damage, thanks to the satellite cells, or muscle stem cells (MuSCs), that implement the adult myogenic program. This program is sustained by both robust intrinsic mechanisms and extrinsic cues coming from the close neighborhood of MuSCs during muscle regeneration. Among the various cell types present in the regenerating muscle, immune cells, and particularly macrophages, exert numerous functions and provide sequential transient niches to support the myogenic program. The adequate orchestration of the delivery of these cues ensures efficient muscle regeneration and full functional recovery. The situation is very different in muscular dystrophies where asynchronous and permanent microinjuries occur, triggering contradictory regenerating cues at the same time in a specific area, that lead to chronic inflammation and fibrogenesis. Here we review the beneficial effects that leukocytes, and particularly macrophages, exert on their neighboring cells during skeletal muscle regeneration after an acute injury. Then, the more complicated (and less beneficial) roles of leukocytes during muscular dystrophies are presented. Finally, we discuss how the inflammatory compartment may be a target to improve muscle regeneration in both acute muscle injury and muscle diseases.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

The role of vascular niche and endothelial cells in organogenesis and regeneration

Highlights: • The vascular niche creates a permissive environment that realize developmental or regenerative programs. • The proximity between endothelium and cells of organs suggests a role of endothelial cells in the organs maturation. • Organs provide cues shaping vascular network structure. The term vascular niche indicate the physical and biochemical microenvironment around blood vessel where endothelial cells, pericytes, and smooth muscle cells organize themselves to form blood vessels and release molecules involved in the recruitment of hematopoietic stem cells, endothelial progenitor cells and mesenchymal stem cells. The vascular niche creates a permissive environment that enables different cell types to realize their developmental or regenerative programs. In this context, the proximity between the endothelium and the new-forming cellular components of organs suggests an essential role of endothelial cells in the organs maturation. Dynamic interactions between specific organ endothelial cells and different cellular conponents are crucial for different organ morphogenesis and function. Conversely, organs provide cues shaping vascular network structure.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

Long noncoding RNA AK023096 interacts with hnRNP-K and contributes to the maintenance of self-renewal in bladder cancer stem-like cells

Highlights: • BCSLCs play a critical role for the high risk of recurrence and we identified that lncRNA-AK023096 was required for controls stemness of BCSLCs. • LncRNA-AK023096 recruits hnRNP-K and epigenetically upregulated SOX2 expression by modulating H3K4 trimethylation of SOX2 promoter. • Overexpression of lncRNA-AK023096 expression in the tumor tissue was significantly associated with high risk of recurrence following TUR-Bt. LncRNA contribution to self-renewal of bladder cancer stem-like cells (CSLCs) remains largely unknown. We investigated the expression profile and biological function of lncRNAs in urothelial CSLCs by microarray analysis. Among these, lncRNA-AK023096 was identified as potentially playing a role in maintaining self-renewal of CSLCs. Knockdown of this transcript inhibited spheroid formation and tumor formation. We found that AK023096 mediates recruitment of hnRNP-K to SOX2 promoter and increases H3K4 trimethylation status on SOX2 promoter, leading to a robust change in SOX2 mRNA and protein levels. Moreover, AK023096 expression in primary tumors was found to be a powerful predictor of recurrence following transurethral resection in patients with nonmuscle-invasive bladder cancer, highlighting the critical role of lncRNA in the bladder cancer regulatory network.

60 APPLIED LIFE SCIENCES↗

NASA NTRS1989

The effects of simulated hypogravity on murine bone marrow cells

Mouse bone marrow cells grown in complete medium at unit gravity were compared with a similar population cultured in conditions that mimic some aspects of microgravity. After the cells adjusted to the conditions that simulated microgravity, they proliferated as fetal or oncogenic populations; their numbers doubled in twelve hour periods. Differentiated subpopulations were depleted from the heterogeneous mixture with time and the undifferentiated hematopoietic stem cells increased in numbers. The cells in the control groups in unit gravity and those in the bioreactors in conditions of microgravity were monitored under a number of parameters. Each were phenotyped as to cell surface antigens using a panel of monoclonal antibodies and flow cytometry. Other parameters compared included: pH, glucose uptake, oxygen consumption and carbon-dioxide production. Nuclear DNA was monitored by flow cytometry. Functional responses were studied by mitogenic stimulation by various lectins. The importance of these findings should have relevance to the space program. Cells should behave predictably in zero gravity; specific populations can be eliminated from diverse populations and other populations isolated. The availability of stem cell populations will enhance both bone marrow and gene transplant programs. Stem cells will permit developmental biologists study the paths of hematopoiesis.

Lawless, Desales↗

DOE OSTI2026

YAP1 Dysfunction Promotes Molecular Properties Linked to Breast Cancer Susceptibility

YAP1 is a cotranscription factor that promotes malignant and stem cell properties in cancer. We previously found that YAP1 dysregulation is associated with aging in human mammary epithelia. With increased age, YAP1 expression changes in luminal epithelial cells, the prospective breast cancer cell of origin. Because age is a significant risk factor for breast cancer, we tested whether YAP1 dysregulation acted early in cancer progression by conferring cellular states associated with increased cancer susceptibility. In this study, we find that with increased age and genetic risk for developing cancer, human breast tissues showed significantly increased YAP1 expression, and cultured primary human mammary epithelial cells (HMEC) showed significantly increased expression of both YAP1 and its transcriptional targets. Increased YAP1 expression in cultured HMEC induced gene expression changes associated with increased cancer susceptibility, such as genes associated with stem cell states, increased telomerase activity, breast cancer progression, and increased age and genetic breast cancer risk. Furthermore, overexpression of YAP1 in post-stasis HMEC—finite lifespan cells that have bypassed a retinoblastoma-mediated senescence barrier—promoted properties related to increased growth potential. We found that YAP1 dysregulation in finite epithelial cells allows for access to gene programs and functions that are typically thought to be restricted to stem cells. We hypothesize that YAP1 acts early in breast cancer progression, long before the development of a tumor, to impose cancer-susceptible molecular states.

YAP1↗

NASA NTRS2001

Establishment of segment polarity in the ectoderm of the leech Helobdella

The segmented ectoderm and mesoderm of the leech arise via a stereotyped cell lineage from embryonic stem cells called teloblasts. Each teloblast gives rise to a column of primary blast cell daughters, and the blast cells generate descendant clones that serve as the segmental repeats of their particular teloblast lineage. We have examined the mechanism by which the leech primary blast cell clones acquire segment polarity - i.e. a fixed sequence of positional values ordered along the anteroposterior axis of the segmental repeat. In the O and P teloblast lineages, the earliest divisions of the primary blast cell segregate anterior and posterior cell fates along the anteroposterior axis. Using a laser microbeam, we ablated single cells from both o and p blast cell clones at stages when the clone was two to four cells in length. The developmental fate of the remaining cells was characterized with rhodamine-dextran lineage tracer. Twelve different progeny cells were ablated, and in every case the ablation eliminated the normal descendants of the ablated cell while having little or no detectable effect on the developmental fate of the remaining cells. This included experiments in which we specifically ablated those blast cell progeny that are known to express the engrailed gene, or their lineal precursors. These findings confirm and extend a previous study by showing that the establishment of segment polarity in the leech ectoderm is largely independent of cell interactions conveyed along the anteroposterior axis. Both intercellular signaling and engrailed expression play an important role in the segment polarity specification of the Drosophila embryo, and our findings suggest that there may be little or no conservation of this developmental mechanism between those two organisms.

NASA Discipline Evolutionary Biology↗

DOE OSTI2021

Glioblastoma cell migration is directed by electrical signals

Electric field (EF) directed cell migration (electrotaxis) is known to occur in glioblastoma multiforme (GBM) and neural stem cells, with key signalling pathways frequently dysregulated in GBM. One such pathway is EGFR/PI3K/Akt, which is down-regulated by peroxisome proliferator activated receptor gamma (PPARγ) agonists. We investigated the effect of electric fields on primary differentiated and glioma stem cell (GSCs) migration, finding opposing preferences for anodal and cathodal migration, respectively. We next sought to determine whether chemically disrupting Akt through PTEN upregulation with the PPARγ agonist, pioglitazone, would modulate electrotaxis of these cells. We found that directed cell migration was significantly inhibited with the addition of pioglitazone in both differentiated GBM and GSCs subtypes. Western blot analysis did not demonstrate any change in PPARγ expression with and without exposure to EF. In summary we demonstrate opposing EF responses in primary GBM differentiated cells and GSCs can be inhibited chemically by pioglitazone, implicating GBM EF modulation as a potential target in preventing tumour recurrence.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

Injectable platelet rich fibrin facilitates hair follicle regeneration by promoting human dermal papilla cell proliferation, migration, and trichogenic inductivity

Hair follicle regeneration has been successful in mice but failed in human being for years. Dermal papilla cells, a specialized mesenchymal stem cell derived from dermal papilla within hair follicles, is considered the key cells for hair follicle regeneration function as both regeneration initiator and regulator. Injectable platelet rich fibrin (i-PRF), a novel biomaterial rich in a variety of growth factors and three-dimensional scaffolds, has shown promising effects on tissue regeneration. In this study, we aimed to evaluate the application of i-PRF in human hair follicle regeneration by examining the biological effects of i-PRF on human dermal papilla cells (hDPCs). Biomaterial compatibility, cell viability, proliferation, migration, alkaline phosphatase activity and trichogenic inductivity were assessed after exposing hDPCs to different concentrations of i-PRF extracts. In addition, we investigated the ultrastructure of i-PRF with all cell components filtered. The results revealed that i-PRF possessing excellent biocompatibility and could significantly promote hDPCs proliferation, migration, and trichogenic inductivity. Furthermore, the concentration of i-PRF is able to remarkably influence hDPCs behavior in a dose-dependent pattern. Different concentrations exhibited differential effects on hDPCs behavior. In general, lower concentration promotes cell proliferation better than higher concentration, while higher concentration promotes cell function better reversely. Best concentration for hDPCs in vitro expending is 1% concentration. 20% concentration is optimal for hair follicle regeneration. In summary, our findings concluded that i-PRF facilitates hair follicle regeneration by promoting human dermal papilla cell proliferation, migration, and trichogenic inductivity.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

CBP/P300 Inhibitors Mitigate Radiation-Induced GI Syndrome by Promoting Intestinal Stem Cell-Mediated Crypt Regeneration

Radiation-induced gastrointestinal syndrome (RIGS) is currently the main cause of death for people exposed to a high dose of irradiation during nuclear incidents, and there is currently no approved effective therapy. Here, we found that CBP/P300 inhibitors, with high efficacy and low toxicity, might be promising radiation mitigators that can cure RIGS.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2020

Transcriptomic and proteomic signatures of stemness and differentiation in the colon crypt

The intestinal epithelium is replaced weekly by non-quiescent stem cells with kinetics that rely on a rapid loss of stemness and choice for secretory or absorptive lineage differentiation. To determine how the cellular transcriptome and proteome changes during these transitions, we developed a new cell sorting method to purify stem cells, secretory and absorptive progenitor cells, and mature, differentiated cells. Transcriptome analyses revealed that as stem cells transition to the progenitor stage, alternative mRNA splicing and polyadenylation dominate changes in the transcriptome. In contrast, as progenitors differentiate into mature cell types, alterations in gene expression and mRNA levels drive the changes. RNA processing targets mRNAs encoding regulators of cell cycle, RNA regulators, cell adhesion, SUMOylation, and Wnt and Notch signaling. Additionally, global proteome profiling of sorted cell populations detected >2,800 proteins and revealed RNA:protein patterns of abundance and correlation. Paired together, these data highlight new potentials for autocrine and feedback regulation and provide new insights into cell state transitions in the crypt.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2024

Protein Structure Inspired Discovery of a Novel Inducer of Anoikis in Human Melanoma

Drug discovery historically starts with an established function, either that of compounds or proteins. This can hamper discovery of novel therapeutics. As structure determines function, we hypothesized that unique 3D protein structures constitute primary data that can inform novel discovery. Using a computationally intensive physics-based analytical platform operating at supercomputing speeds, we probed a high-resolution protein X-ray crystallographic library developed by us. For each of the eight identified novel 3D structures, we analyzed binding of sixty million compounds. Top-ranking compounds were acquired and screened for efficacy against breast, prostate, colon, or lung cancer, and for toxicity on normal human bone marrow stem cells, both using eight-day colony formation assays. Effective and non-toxic compounds segregated to two pockets. One compound, Dxr2-017, exhibited selective anti-melanoma activity in the NCI-60 cell line screen. In eight-day assays, Dxr2-017 had an IC50 of 12 nM against melanoma cells, while concentrations over 2100-fold higher had minimal stem cell toxicity. Dxr2-017 induced anoikis, a unique form of programmed cell death in need of targeted therapeutics. Our findings demonstrate proof-of-concept that protein structures represent high-value primary data to support the discovery of novel acting therapeutics. This approach is widely applicable.

Oncology↗

NASA NTRS1990

Coupling of solute transport and cell expansion in pea stems

As cells expand and are displaced through the elongation zone of the epicotyl of etiolated pea (Pisum sativum L. var Alaska) seedlings, there is little net dilution of the cell sap, implying a coordination between cell expansion and solute uptake from the phloem. Using [14C] sucrose as a phloem tracer (applied to the hypogeous cotyledons), the pattern of label accumulation along the stem closely matched the growth rate pattern: high accumulation in the growing zone, little accumulation in nongrowing regions. Several results suggest that a major portion of phloem contents enters elongating cells through the symplast. We propose that the coordination between phloem transport and cell expansion is accomplished via regulatory pathways affecting both plasmodesmata conductivity and cell expansion.

NASA Discipline Plant Biology↗

DOE OSTI2023

Cryo-EM analyses of KIT and oncogenic mutants reveal structural oncogenic plasticity and a target for therapeutic intervention

The receptor tyrosine kinase KIT and its ligand stem cell factor (SCF) are required for the development of hematopoietic stem cells, germ cells, and other cells. A variety of human cancers, such as acute myeloid leukemia, gastrointestinal stromal tumor, and mast cell leukemia, are driven by somatic gain-of-function KIT mutations. Here, we report cryo electron microscopy (cryo-EM) structural analyses of full-length wild-type and two oncogenic KIT mutants, which show that the overall symmetric arrangement of the extracellular domain of ligand-occupied KIT dimers contains asymmetric D5 homotypic contacts juxtaposing the plasma membrane. Mutational analysis of KIT reveals in D5 region an “Achilles heel” for therapeutic intervention. A ligand-sensitized oncogenic KIT mutant exhibits a more comprehensive and stable D5 asymmetric conformation. A constitutively active ligand-independent oncogenic KIT mutant adopts a V-shaped conformation solely held by D5-mediated contacts. Binding of SCF to this mutant fully restores the conformation of wild-type KIT dimers, including the formation of salt bridges responsible for D4 homotypic contacts and other hallmarks of SCF-induced KIT dimerization. These experiments reveal an unexpected structural plasticity of oncogenic KIT mutants and a therapeutic target in D5.

60 APPLIED LIFE SCIENCES↗

NASA NTRS2002

Cellular and molecular responses to increased skeletal muscle loading after irradiation

Irradiation of rat skeletal muscles before increased loading has been shown to prevent compensatory hypertrophy for periods of up to 4 wk, possibly by preventing satellite cells from proliferating and providing new myonuclei. Recent work suggested that stem cell populations exist that might allow irradiated muscles to eventually hypertrophy over time. We report that irradiation essentially prevented hypertrophy in rat muscles subjected to 3 mo of functional overload (OL-Ir). The time course and magnitude of changes in cellular and molecular markers of anabolic and myogenic responses were similar in the OL-Ir and the contralateral nonirradiated, overloaded (OL) muscles for the first 3-7 days. These markers then returned to control levels in OL-Ir muscles while remaining elevated in OL muscles. The number of myonuclei and amount of DNA were increased markedly in OL but not OL-Ir muscles. Thus it appears that stem cells were not added to the irradiated muscles in this time period. These data are consistent with the theory that the addition of new myonuclei may be required for compensatory hypertrophy in the rat.

Non-NASA Center↗

DOE OSTI2021

Temporal responsiveness of adipose-derived stem/stromal cell immune plasticity

Highlights: • Adipose-derived stem cells modulate immune responses in a plastic manner. • The persistence of pro- and anti-inflammatory phenotypes was explored over time. • IL-6 was present at all time points; IDO1 was induced after cytokine stimulation. • Phenotypes persisted 96–168 h after returning to control conditions. • Macrophages showed reaction to ASC culture but without time effect. We determined the role of time in adipose-derived stem/stromal cell (ASC) response to a model inflammatory environment. ASCs and other mesenchymal stem/stromal cells exhibit immune plasticity. We evaluated the persistence of pro- and anti-inflammatory phenotypes for ASCs exposed to a sustained or pulse inflammatory stimulus. Using qPCR, flow cytometry, and immunocytochemistry, we monitored the temporal expression and up-regulation patterns of a pro-inflammatory gene (caspase 1), a pleiotropic gene/protein (interleukin 6, IL-6), and an anti-inflammatory gene/protein (indoleamine 2, 3-dioxygenase, IDO1) after exposing ASCs to the cytokines tumor necrosis factor-α and interferon-γ. In response to sustained cytokine stimulation, we discovered that time played a role in the balance of pro- and anti-inflammatory ASC phenotypes. IL-6 was present at all time points for both cytokine-stimulated and non-stimulated conditions, whereas IDO1 was heterogeneously up-regulated in stimulated conditions at later time points. After a pulse stimulus, ASC immunoresponse remained consistent for 96–168 h. As a final measure of immune plasticity, we cultured cytokine-stimulated ASCs with blood-derived macrophages to observe macrophage polarization. While the presence of ASCs altered macrophage phenotype, there was no dependency on the length of ASC cytokine exposure time.

60 APPLIED LIFE SCIENCES↗

NASA NTRSDate not supplied

A Novel Bone Marrow Single Cell Atlas of Mechanotransduction in Microgravity, Normal Gravity, Exercise, and Hindlimb Unloading for WT and CDKN1A-Null Regenerative Mice

Mechanical loading of adult stem cell progenitors is a key factor in modulating their proliferation, differentiation, and tissue regenerative potential, with loading generally promoting tissue formation and unloading mediating tissue loss. To address the role of mechanotransduction in maintaining stem cell-based tissue regenerative health, we generated a single cell transcriptomic atlas mapping responses of femur bone marrow mesenchymal and hematopoietic lineages to a range of altered mechanical loading conditions, both in WT B1629SF2/J mice as well as the p21/CDKN1A-null regenerative mice. We selected the femur marrow compartment as a model because of the diversity and high numbers of stem cell progenitor stages present, and because it undergoes static and cyclic hydrostatic pressure loading associated with weight-bearing and ambulation. Our study included normally loaded mice at 1g, unloading in microgravity during spaceflight as well as tail suspension hindlimb unloading, and voluntary running wheel exercise. Basal, one-year natural aging, and habitat controls were also conducted. Overall, the atlas encompasses 18 different experimental conditions with N=3 mice per condition and includes more than 500,000 single cell expressomes. Key specific findings include: increased mature reticulocyte populations in aging and unloading mice compared to active mice; greater hematopoietic and mesenchymal differentiating progenitors cluster identification in CDKN1A-null samples, especially the exercise model; distinct pseudotime cell trajectory shifts in the hematopoietic lineage for spaceflight and unloaded mice; and shifts in monocytic cell populations toward osteoclastic bone degenerative lineages in unloading and spaceflight samples. Overall mechanical loading shows increased marrow progenitor population differentiation while unloading is associated with increased CDKN1A expression and maintenance of marrow population stemness. Deletion of CDKN1A appears to remove a negative check on progenitor lineages commitment to differentiation. Finally, the Bone Marrow Mechanotransduction Single Cell Atlas will serve as a reference tool for studying marrow regenerative responses across a range of mechanical environments as they relate to CDKN1A status.

single-cell↗