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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 37 records · Page 2
All sourcesNASA NTRSDOE OSTI
NASA NTRS2004

Modeled Microgravity Disrupts Collagen I/Integrin Signaling During Osteoblastic Differentiation of Human Mesenchymal Stem Cells

Spaceflight leads to reduced bone mineral density in weight bearing bones that is primarily attributed to a reduction in bone formation. We have previously demonstrated severely reduced osteoblastogenesis of human mesenchymal stem cells (hMSC) following seven days culture in modeled microgravity. One potential mechanism for reduced osteoblastic differentiation is disruption of type I collagen-integrin interactions and reduced integrin signaling. Integrins are heterodimeric transmembrane receptors that bind extracellular matrix proteins and produce signals essential for proper cellular function, survival, and differentiation. Therefore, we investigated the effects of modeled microgravity on integrin expression and function in hMSC. We demonstrate that seven days of culture in modeled microgravity leads to reduced expression of the extracellular matrix protein, type I collagen (Col I). Conversely, modeled microgravity consistently increases Col I-specific alpha2 and beta1 integrin protein expression. Despite this increase in integrin sub-unit expression, autophosphorylation of adhesion-dependent kinases, focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK2), is significantly reduced. Activation of Akt is unaffected by the reduction in FAK activation. However, reduced downstream signaling via the Ras-MAPK pathway is evidenced by a reduction in Ras and ERK activation. Taken together, our findings indicate that modeled microgravity decreases integrin/MAPK signaling, which likely contributes to the observed reduction in osteoblastogenesis.

Meyers, Valerie E.↗
NASA NTRS2015

Effects of Angular Frequency During Clinorotation on Mesenchymal Stem Cell Morphology and Migration

Background/Objectives: Ground-based microgravity simulation can reproduce the apparent effects of weightlessness in spaceflight using clinostats that continuously reorient the gravity vector on a specimen, creating a time-averaged nullification of gravity. In this work, we investigated the effects of clinorotation speed on the morphology, cytoarchitecture, and migration behavior of human mesenchymal stem cells (hMSCs). Methods: We compared cell responses at clinorotation speeds of 0, 30, 60, and 75 rpm over 8 hours in a recently developed lab-on-chip-based clinostat system. Time lapse light microscopy was used to visualize changes in cell morphology during and after cessation of clinorotation. Cytoarchitecture was assessed by actin and vinculin staining, and chemotaxis was examined using time lapse light microscopy of cells in NGF (100 ng/ml) gradients. Results: Among clinorotated groups, cell area distributions indicated a greater inhibition of cell spreading with higher angular frequency (p is less than 0.005), though average cell area at 30 rpm after 8 hours became statistically similar to control (p = 0.794). Cells at 75rpm clinorotation remained viable and were able to re-spread after clinorotation. In chemotaxis chambers clinorotation did not alter migration patterns in elongated cells, but most clinorotated cells exhibited cell retraction, which strongly compromised motility.

microgravity↗
NASA NTRS2003

Multilineage differentiation of rhesus monkey embryonic stem cells in three-dimensional culture systems

In the course of normal embryogenesis, embryonic stem (ES) cells differentiate along different lineages in the context of complex three-dimensional (3D) tissue structures. In order to study this phenomenon in vitro under controlled conditions, 3D culture systems are necessary. Here, we studied in vitro differentiation of rhesus monkey ES cells in 3D collagen matrixes (collagen gels and porous collagen sponges). Differentiation of ES cells in these 3D systems was different from that in monolayers. ES cells differentiated in collagen matrixes into neural, epithelial, and endothelial lineages. The abilities of ES cells to form various structures in two chemically similar but topologically different matrixes were different. In particular, in collagen gels ES cells formed gland-like circular structures, whereas in collagen sponges ES cells were scattered through the matrix or formed aggregates. Soluble factors produced by feeder cells or added to the culture medium facilitated ES cell differentiation into particular lineages. Coculture with fibroblasts in collagen gel facilitated ES cell differentiation into cells of a neural lineage expressing nestin, neural cell adhesion molecule, and class III beta-tubulin. In collagen sponges, keratinocytes facilitated ES cell differentiation into cells of an endothelial lineage expressing factor VIII. Exogenous granulocyte-macrophage colony-stimulating factor further enhanced endothelial differentiation. Thus, both soluble factors and the type of extracellular matrix seem to be critical in directing differentiation of ES cells and the formation of tissue-like structures. Three-dimensional culture systems are a valuable tool for studying the mechanisms of these phenomena.

Pluripotent Stem Cells/cytology/physiology↗
NASA NTRS1980

Differentiation and radiosensitivity of hemopoietic stem cells of mice during hypokinesia

The potential for differentiation and radiosensitivity of the stem hemopoietic cells (KOE) under conditions of initial and later hypokinesia is examined. It is established that in the initial period of hypokinesia (3 days) when a stress reaction prevails, changes occur in the erythroid differentiation and radiosensitivity of KOE. This effect is associated with redistribution of T-lymphocytes that increase in number in the bone marrow of mice during hypokinesia. At later periods of hypokinesia (30 days) when changes in the organism are related to hypokinesia proper, differentiation and radiosensitivity of KOE were normalized.

Shvets, V. N.↗
NASA NTRS2006

Space Exploration: A Risk for Neural Stem Cells

During spaceflights beyond low Earth orbit, astronauts are exposed to potentially carcinogenic and tissue damaging galactic cosmic rays, solar proton events, and secondary radiation that includes neutrons and recoil nuclei produced by nuclear reactions in spacecraft walls or in tissue (1). Such radiation risk may present a significant health risk for human exploration of the moon and Mars. Emerging evidence that generation of new neurons in the adult brain may be essential for learning, memory, and mood (2) and that radiation is deleterious to neurogenesis (3-5) underscores a previously unappreciated possible risk to the cognitive functions and emotional stability of astronauts exposed to radiation in space. Here we use a novel reporter mouse line to identify at-risk populations of stem and progenitor cells in the brain and find, unexpectedly, that quiescent stem-like cells (rather than their rapidly dividing progeny) in the hippocampus constitute the most vulnerable cell population. This finding raises concerns about the possible risks facing astronauts on long duration space missions.

Encinas, Juan M.↗
NASA NTRS1990

A study of murine bone marrow cells cultured in bioreactors which create an environment which simulated microgravity

Previous research indicated that mouse bone marrow cells could be grown in conditions of simulated microgravity. This environment was created in rotating bioreactor vessels. On three attempts mouse cells were grown successfully in the vessels. The cells reached a stage where the concentrations were doubling daily. Phenotypic analysis using a panel of monoclonal antibodies indicated that the cell were hematopoietic pluripotent stem cells. One unsuccessful attempt was made to reestablish the immune system in immunocompromised mice using these cells. Since last summer, several unsuccessful attempts were made to duplicate these results. It was determined by electron microscopy that the cells successfully grown in 1989 contained virus particles. It was suggested that these virally parasitized cells had been immortalized. The work of this summer is a continuation of efforts to grow mouse bone marrow in these vessels. A number of variations of the protocol were introduced. Certified pathogen free mice were used in the repeat experiments. In some attempts the medium of last summer was used; in others Dexture Culture Medium containing Iscove's Medium supplemented with 20 percent horse serum and 10-6 M hydrocortisone. Efforts this summer were directed solely to repeating the work of last summer. Plans were made for investigations if stem cells were isolated. Immortalization of the undifferentiated stem cell would be attempted by transfection with an oncogenic vector. Selective differentiation would be induced in the stem cell line by growing it with known growth factors and immune response modulators. Interest is in identifying any surface antigens unique to stem cells that would help in their characterization. Another goal was to search for markers on stem cells that would distinguish them from stem cells committed to a particular lineage. If the undifferentiated hematopoietic stem cell was obtained, the pathways that would terminally convert it to myeloid, lyphoid, erythroid, or other cell lines would be studied. Transfection with a known gene would be attempted and then conversion to a terminally identifiable cell.

Lawless, Brother Desales↗
NASA NTRS2021

Topical: Stem Cell-Based Tissue Regenerative Health in Space

The maintenance of healthy adult tissues in mammals requires a complex homeostasis of molecular, cellular, tissue, and metabolic processes which are fundamentally different from the development and aging processes that bookend life. Cellular homeostasis in the adult requires molecular maintenance and repair of non-dividing cells such as cardiomyocytes and neurons, but also stem cell-based tissue regeneration via direct replacement of cell loss, such as in the blood, immune system, bone, skin, liver, intestine, and other tissues. Because stem cell-based tissue regenerative health requires constant proliferation and differentiation of stem cell progenitors in the bone marrow, and other adult stem cell niches, it is uniquely sensitive to the stresses of spaceflight including exposure to space radiation and mechanical unloading in microgravity. A key central hypothesis in this field is that those spaceflight stress factors can have profound negative effects on long-term tissue regenerative health mediated by adult stem cells, and that unmitigated, they may lead to premature tissue aging and functional failure. Specifically, it is thought that mechanical unloading due to lack of weight-bearing in space reduces mitogenic mechanotransduction necessary to promote adult stem cell proliferation and differentiation, and that space radiation can also lead to activation of cell cycle arrest mechanisms, further reducing adult stem cell proliferation. These hypotheses are being tested in low earth orbit(LEO)using a variety of cellular and whole organism tissue model systems, suggesting that spaceflight consistently interferes with stem cell tissue regenerative processes such as in mammalian embryoid bodies, regenerating newt tails, and mouse bone marrow hematopoietic and osteoprogenitor cells. Furthermore, potential molecular mechanisms integrating both space radiation and mechanical disuse via oxidative stress and the cell cycle inhibitor Cdkn1aare now under study using single cell (scRNAseq) expressome analysis of bone marrow osteoprogenitors, both under stretch loading, and spaceflight conditions including in various mouse transgenic null backgrounds relevant to these mechanisms. Future work in the area of tissue regenerative health in space for the coming decade should seek to understand the responses the various tissue regenerative stem cell niches in humans and relevant model organisms, and how they respond to long-term exposure to the space environment. Special emphases of future work should be on how regenerative deficits in whole-organism stem cell niches may lead to tissue degeneration and premature aging, and on the long-term proliferation and differentiation of stem cell derived tissue organoid models in the deep space environment outside of LEO.

Eduardo A C Almeida↗
NASA NTRS2018

Stem Cell-Based Regenerative Health in Microgravity

The research of Dr. Almeida's Lab at NASA Ames focuses on the effects of microgravity mechanical unloading on stem-cell-based tissue regeneration. The research focuses on testing the broad hypothesis that mechanical load from gravity at 1 g is required for normal adult stem cell proliferation and differentiation during tissue regeneration. Research from the lab has provides evidence supporting the hypothesis in various biological models, including newt tail regeneration, mouse bone and bone marrow in whole animals, and mouse embryonic stem cells all exposed to microgravity during spaceflight. Using these models, the lab has identified overexpression of the cell cycle inhibitor p21/CDKN1a as a candidate molecular mediator mechanism of bone marrow mesenchymal and hematopoietic lineage tissue regenerative arrest in microgravity. The labis currently focused on using p21/CDKN1a null mouse and cell culture approaches in microgravity to test the gravity tissue regeneration hypothesis.

stem cells microgravity regeneration↗
NASA NTRS2005

Tissue Engineering Using Transfected Growth-Factor Genes

A method of growing bioengineered tissues includes, as a major component, the use of mammalian cells that have been transfected with genes for secretion of regulator and growth-factor substances. In a typical application, one either seeds the cells onto an artificial matrix made of a synthetic or natural biocompatible material, or else one cultures the cells until they secrete a desired amount of an extracellular matrix. If such a bioengineered tissue construct is to be used for surgical replacement of injured tissue, then the cells should preferably be the patient s own cells or, if not, at least cells matched to the patient s cells according to a human-leucocyteantigen (HLA) test. The bioengineered tissue construct is typically implanted in the patient's injured natural tissue, wherein the growth-factor genes enhance metabolic functions that promote the in vitro development of functional tissue constructs and their integration with native tissues. If the matrix is biodegradable, then one of the results of metabolism could be absorption of the matrix and replacement of the matrix with tissue formed at least partly by the transfected cells. The method was developed for articular chondrocytes but can (at least in principle) be extended to a variety of cell types and biocompatible matrix materials, including ones that have been exploited in prior tissue-engineering methods. Examples of cell types include chondrocytes, hepatocytes, islet cells, nerve cells, muscle cells, other organ cells, bone- and cartilage-forming cells, epithelial and endothelial cells, connective- tissue stem cells, mesodermal stem cells, and cells of the liver and the pancreas. Cells can be obtained from cell-line cultures, biopsies, and tissue banks. Genes, molecules, or nucleic acids that secrete factors that influence the growth of cells, the production of extracellular matrix material, and other cell functions can be inserted in cells by any of a variety of standard transfection techniques.

Madry, Henning↗
NASA NTRS2006

Radiation-Induced Leukemia at Doses Relevant to Radiation Therapy: Modeling Mechanisms and Estimating Risks

Because many cancer patients are diagnosed earlier and live longer than in the past, second cancers induced by radiation therapy have become a clinically significant issue. An earlier biologically based model that was designed to estimate risks of high-dose radiation induced solid cancers included initiation of stem cells to a premalignant state, inactivation of stem cells at high radiation doses, and proliferation of stem cells during cellular repopulation after inactivation. This earlier model predicted the risks of solid tumors induced by radiation therapy but overestimated the corresponding leukemia risks. Methods: To extend the model to radiation-induced leukemias, we analyzed in addition to cellular initiation, inactivation, and proliferation a repopulation mechanism specific to the hematopoietic system: long-range migration through the blood stream of hematopoietic stem cells (HSCs) from distant locations. Parameters for the model were derived from HSC biologic data in the literature and from leukemia risks among atomic bomb survivors v^ ho were subjected to much lower radiation doses. Results: Proliferating HSCs that migrate from sites distant from the high-dose region include few preleukemic HSCs, thus decreasing the high-dose leukemia risk. The extended model for leukemia provides risk estimates that are consistent with epidemiologic data for leukemia risk associated with radiation therapy over a wide dose range. For example, when applied to an earlier case-control study of 110000 women undergoing radiotherapy for uterine cancer, the model predicted an excess relative risk (ERR) of 1.9 for leukemia among women who received a large inhomogeneous fractionated external beam dose to the bone marrow (mean = 14.9 Gy), consistent with the measured ERR (2.0, 95% confidence interval [CI] = 0.2 to 6.4; from 3.6 cases expected and 11 cases observed). As a corresponding example for brachytherapy, the predicted ERR of 0.80 among women who received an inhomogeneous low-dose-rate dose to the bone marrow (mean = 2.5 Gy) was consistent with the measured ERR (0.62, 95% Cl =-0.2 to 1.9). Conclusions: An extended, biologically based model for leukemia that includes HSC initiation, inactivation, proliferation, and, uniquely for leukemia, long-range HSC migration predicts, %Kith reasonable accuracy, risks for radiationinduced leukemia associated with exposure to therapeutic doses of radiation.

Shuryak, Igor↗
NASA NTRS1999

Tissue-engineered human bioartificial muscles expressing a foreign recombinant protein for gene therapy

Murine skeletal muscle cells transduced with foreign genes and tissue engineered in vitro into bioartificial muscles (BAMs) are capable of long-term delivery of soluble growth factors when implanted into syngeneic mice (Vandenburgh et al., 1996b). With the goal of developing a therapeutic cell-based protein delivery system for humans, similar genetic tissue-engineering techniques were designed for human skeletal muscle stem cells. Stem cell myoblasts were isolated, cloned, and expanded in vitro from biopsied healthy adult (mean age, 42 +/- 2 years), and elderly congestive heart failure patient (mean age, 76 +/- 1 years) skeletal muscle. Total cell yield varied widely between biopsies (50 to 672 per 100 mg of tissue, N = 10), but was not significantly different between the two patient groups. Percent myoblasts per biopsy (73 +/- 6%), number of myoblast doublings prior to senescence in vitro (37 +/- 2), and myoblast doubling time (27 +/- 1 hr) were also not significantly different between the two patient groups. Fusion kinetics of the myoblasts were similar for the two groups after 20-22 doublings (74 +/- 2% myoblast fusion) when the biopsy samples had been expanded to 1 to 2 billion muscle cells, a number acceptable for human gene therapy use. The myoblasts from the two groups could be equally transduced ex vivo with replication-deficient retroviral expression vectors to secrete 0.5 to 2 microg of a foreign protein (recombinant human growth hormone, rhGH)/10(6) cells/day, and tissue engineered into human BAMs containing parallel arrays of differentiated, postmitotic myofibers. This work suggests that autologous human skeletal myoblasts from a potential patient population can be isolated, genetically modified to secrete foreign proteins, and tissue engineered into implantable living protein secretory devices for therapeutic use.

Non-NASA Center↗
NASA NTRS2000

Insulin-like growth factor-I extends in vitro replicative life span of skeletal muscle satellite cells by enhancing G1/S cell cycle progression via the activation of phosphatidylinositol 3'-kinase/Akt signaling pathway

Interest is growing in methods to extend replicative life span of non-immortalized stem cells. Using the insulin-like growth factor I (IGF-I) transgenic mouse in which the IGF-I transgene is expressed during skeletal muscle development and maturation prior to isolation and during culture of satellite cells (the myogenic stem cells of mature skeletal muscle fibers) as a model system, we elucidated the underlying molecular mechanisms of IGF-I-mediated enhancement of proliferative potential of these cells. Satellite cells from IGF-I transgenic muscles achieved at least five additional population doublings above the maximum that was attained by wild type satellite cells. This IGF-I-induced increase in proliferative potential was mediated via activation of the phosphatidylinositol 3'-kinase/Akt pathway, independent of mitogen-activated protein kinase activity, facilitating G(1)/S cell cycle progression via a down-regulation of p27(Kip1). Adenovirally mediated ectopic overexpression of p27(Kip1) in exponentially growing IGF-I transgenic satellite cells reversed the increase in cyclin E-cdk2 kinase activity, pRb phosphorylation, and cyclin A protein abundance, thereby implicating an important role for p27(Kip1) in promoting satellite cell senescence. These observations provide a more complete dissection of molecular events by which increased local expression of a growth factor in mature skeletal muscle fibers extends replicative life span of primary stem cells than previously known.

NASA Discipline Musculoskeletal↗
NASA NTRS2006

Bucky Paper as a Support Membrane in Retinal Cell Transplantation

A method for repairing a retinal system of an eye, using bucky paper on which a plurality of retina pigment epithelial cells and/or iris pigment epithelial cells and/or stem cells is deposited, either randomly or in a selected cell pattern. The cell-covered bucky paper is positioned in a sub-retinal space to transfer cells to this space and thereby restore the retina to its normal functioning, where retinal damage or degeneration, such as macular degeneration, has occurred.

Loftus, David J.↗
NASA NTRS2004

Transplanting Retinal Cells using Bucky Paper for Support

A novel treatment for retinal degenerative disorders involving transplantation of cells into the eye is currently under development at NASA Ames Research Center and Stanford University School of Medicine. The technique uses bucky paper as a support material for retinal pigment epithelial (RPE) cells, iris pigment epithelial (IPE) cells, and/or stem cells. This technology is envisioned as a treatment for age-related macular degeneration, which is the leading cause of blindness in persons over age 65 in Western nations. Additionally, patients with other retinal degenerative disorders, such as retinitis pigmentosa, may be treated by this strategy. Bucky paper is a mesh of carbon nanotubes (CNTs), as shown in Figure 1, that can be made from any of the commercial sources of CNTs. Bucky paper is biocompatible and capable of supporting the growth of biological cells. Because bucky paper is highly porous, nutrients, oxygen, carbon dioxide, and waste can readily diffuse through it. The thickness, density, and porosity of bucky paper can be tailored in manufacturing. For transplantation of cells into the retina, bucky paper serves simultaneously as a substrate for cell growth and as a barrier for new blood vessel formation, which can be a problem in the exudative type of macular degeneration. Bucky paper is easily handled during surgical implantation into the eye. Through appropriate choice of manufacturing processes, bucky paper can be made relatively rigid yet able to conform to the retina when the bucky paper is implanted. Bucky paper offers a distinct advantage over other materials that have been investigated for retinal cell transplantation - lens capsule and Descemet's membrane - which are difficult to handle during surgery because they are flimsy and do not stay flat.

Loftus, David J.↗
NASA NTRS2015

Aligned and Electrospun Piezoelectric Polymer Fiber Assembly and Scaffold

A scaffold assembly and related methods of manufacturing and/or using the scaffold for stem cell culture and tissue engineering applications are disclosed which at least partially mimic a native biological environment by providing biochemical, topographical, mechanical and electrical cues by using an electroactive material. The assembly includes at least one layer of substantially aligned, electrospun polymer fiber having an operative connection for individual voltage application. A method of cell tissue engineering and/or stem cell differentiation uses the assembly seeded with a sample of cells suspended in cell culture media, incubates and applies voltage to one or more layers, and thus produces cells and/or a tissue construct. In another aspect, the invention provides a method of manufacturing the assembly including the steps of providing a first pre-electroded substrate surface; electrospinning a first substantially aligned polymer fiber layer onto the first surface; providing a second pre-electroded substrate surface; electrospinning a second substantially aligned polymer fiber layer onto the second surface; and, retaining together the layered surfaces with a clamp and/or an adhesive compound.

Scott-Carnell, Lisa A.↗