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NASA NTRS2007

Comparative MicroRNA Expression Patterns in Fibroblasts after Low and High Doses of Low-LET Radiation Exposure

Exposure to ionizing radiation causes DNA damage to cells, and provokes a plethora of cellular responses controlled by unique gene-directed signaling pathways. MicroRNAs (miRNAs) are small (~22-nucleotide), non-coding RNAs which functionally silence gene expression by either degrading the messages or inhibiting translation. Here we investigate radiation-dependent changes in these negative regulators by comparing the expression patterns of all 462 known human miRNAs in fibroblasts, after exposure to low (0.1 Gy) or high (2 Gy) doses of X-rays at 30 min, 2, 6 and 24 hrs post-treatment. The expression patterns of microRNAs after low and high doses of radiation show a similar qualitative down-regulation trend at early (0.5 hr) and late (24 hr) time points, with a quantitatively steeper slope following the 2 Gy exposures. Interestingly, an interruption of this downward trend is observed after the 2 Gy exposure, i.e. a significant up-regulation of microRNAs at 2 hrs, then reverting to the downward trend by 6 hrs; this interruption at the intermediate time point was not observed with the 0.1 Gy exposure. At the early time point (0.5 hr), candidate gene targets of selected down-regulated microRNAs, common to both 0.1 and 2 Gy exposures, were those functioning in chromatin remodeling. Candidate target genes of unique up-regulated microRNAs seen at a 2 hr intermediate time point, after the 2 Gy exposure only, are those involved in cell death signaling. Finally, putative target genes of down-regulated microRNAs seen at the late (24 hr) time point after either doses of radiation are those involved in the up-regulation of DNA repair, cell signaling and homeostasis. Thus we hypothesize that after radiation exposure, microRNAs acting as hub negative regulators for unique signaling pathways needed to be down-regulated so as to de-repress their target genes for the proper cellular responses, including DNA repair and cell maintenance. The unique microRNAs up-regulated at 2 hr after 2 Gy suggest the cellular response to functionally suppress the apoptotic death signaling reflex after exposure to high dose radiation. Further analyses with transcriptome and global proteomic profiling will validate the reciprocal expression of signature microRNAs selected in our radiation-exposed cells, and their candidate target gene families, and test our hypothesis that unique radiation-specific microRNAs are keys in governing signaling responses for damage control of this environmental hazard.

Maes, Olivier C.↗

NASA NTRS2006

The Role of Non-Targeted Effects as Mediators in the Biological Effects of Proton Irradiation

In recent years, the hypothesis that non-DNA targets are primary initiators and mediators of the biological effects of ionizing radiation, such as proton beams and heavy ions, has gained much interest. These phenomena have been denoted as non-targeted or bystander effects to distinguish them from the more traditionally studied model that focuses on direct damage to DNA causing chromosomal rearrangements and mutations as causative of most biological endpoints such as cell killing, tissue damage, and cancer. We review cellular and extra-cellular structures and signal transduction pathways that have been implemented in these recent studies. Non-targeted effects of interest include oxidative damage to the cytoplasm and mitochondria, disruption of the extra-cellular matrix, and modification of cytokine signaling including TGF-beta, and gap junction communication. We present an introduction to these targets and pathways, and contrast there role with DNA damage pathways.

Cucinotta, Francis A.↗

NASA NTRS2010

Radioadaptive Cytoprotective Pathways in the Mouse Retina

Exposure to cosmic radiation implies a risk of tissue degeneration. Radiation retinopathy is a complication of radiotherapy and exhibits common features with other retinopathies and neuropathies. Exposure to a low radiation dose elicits protective cellular events (radioadaptive response), reducing the stress of a subsequent higher dose. To assess the risk of radiation-induced retinal changes and the extent to which a small priming dose reduces this risk, we used a mouse model exposed to a source of Cs-137-gamma radiation. Gene expression profiling of retinas from non-irradiated control C57BL/6J mice (C) were compared to retinas from mice treated with a low 50 mGy dose (LD), a high 6 Gy dose (HD), and a combined treatment of 50 mGy (priming) and 6 Gy (challenge) doses (LHD). Whole retina RNA was isolated and expression analysis for selected genes performed by RTqPCR. Relevant target genes associated with cell death/survival, oxidative stress, cellular stress response and inflammation pathways, were analyzed. Cellular stress response genes were upregulated at 4 hr after the challenge dose in LHD retinas (Sirt1: 1.5 fold, Hsf1: 1.7 fold, Hspa1a: 2.5 fold; Hif1a: 1.8 fold, Bag1: 1.7). A similar trend was observed in LD animals. Most antioxidant enzymes (Hmox1, Sod2, Prdx1, Cygb, Cat1) and inflammatory mediators (NF B, Ptgs2 and Tgfb1) were upregulated in LHD and LD retinas. Expression of the pro-survival gene Bcl2 was upregulated in LD (6-fold) and LHD (4-fold) retinas. In conclusion, cytoprotective gene networks activation in the retina suggests a radioadaptive response to a priming irradiation dose, with mitigation of the deleterious effects of a subsequent high dose exposure. The enhancement of these cytoprotective mechanisms has potential value as a countermeasure to ocular alterations caused by radiation alone or in combination with other factors in spaceflight environments.

Zanello, Susana B.↗

NASA NTRS2011

Pilot Study: Unique Response of Bone Tissue During an Investigation of Radio-Adaptive Effects in Mice

PURPOSE: We obtained bone tissue to evaluate the collateral effects of experiments designed to investigate molecular mechanisms of radio-adaptation in a mouse model. Radio-adaptation describes a process by which the prior exposure to low dose radiation can protect against the toxic effect of a subsequent high dose exposure. In the radio-adaptation experiments, C57Bl/6 mice were exposed to either a Sham or a priming Low Dose (5 cGy) of Cs-137 gamma rays before being exposed to either a Sham or High Dose (6 Gy) 24 hours later. ANALYSIS: Bone tissue were obtained from two experiments where mice were sacrificed at 3 days (n=3/group, 12 total) and at 14 days (n=6/group, 24 total) following high dose exposure. Tissues were analyzed to 1) evaluate a radio-adaptive response in bone tissue and 2) describe cellular and microstructural effects for two skeletal sites with different rates of bone turnover. One tibia and one lumbar vertebrae (LV2), collected at the 3-day time-point, were analyzed by bone histomorphometry and micro-CT to evaluate the cellular response and any evidence of microarchitectural impact. Likewise, tibia and LV2, collected at the 14-day time-point, were analyzed by micro-CT alone to evaluate resulting changes to bone structure and microarchitecture. The data were analyzed by 2-way ANOVA to evaluate the effects of the priming low dose radiation, of the high dose radiation, and of any interaction between the priming low and high doses of radiation. Bone histomorphometry was performed in the cancellous bone (aka trabecular bone) compartments of the proximal tibial metaphysis and of LV2. RESULTS: Cellular Response @ 3 Days The priming Low Dose radiation decreased osteoblast-covered bone perimeter in the proximal tibia and the total cell density in the bone marrow in the LV2. High Dose radiation, regardless of prior exposure to priming dose, dramatically reduced total cell density in bone marrow of both the long bone and vertebra. However, in the proximal tibia, High Dose radiation increased the osteoclast-covered bone perimeters, the density of adipocytes in bone marrow, and the area of bone marrow occupied by fat cells -- while in the LV2, adipocytes were rare and not stimulated by High Dose radiation. In an unexpected response, High Dose radiation dramatically increased (10-fold) osteoblast-covered bone perimeter in the LV2.

Sibonga, J. D.↗

NASA NTRS2011

Contribution of Spaceflight Environmental Factors to Vision Risks

The risk of visual impairment and elevated intracranial pressure as a result of low-earth orbit microgravity exposure has directed our attention and research efforts to the eye. While the alterations observed in astronauts returning from long duration missions include vision and neuroanatomical changes observed by non-invasive methods, other effects and subsequent tissue responses at the molecular and cellular level can only be studied by accessing the tissue itself. As a result of this need, several studies are currently taking place within the Human and Health Countermeasures Element (HHC) that use animal models for eye research. The rodent eye has many similarities to the human eye, and both rats and mice have historically been used as models of human eye disease, aiding in the identification of the disease genes, elucidation of mechanisms of disease, as well as in the assessment of therapeutic treatments. These studies attempt to answer two central questions in the etiology of possible vision alterations in the environment of space exploration missions. The first is: what effects and response mechanisms take place in the different eye structures at the cellular and molecular level? The second question is directed to elucidate the contribution of the various environmental stressors (radiation, nutrition, fluid shift) to these effects. Collaborative approaches with internal and external investigators have allowed performing these studies in a most cost-effective fashion, providing preliminary data and laying the bases for testing further hypotheses in future and specifically designed animal experiments. From a study centered on the radioadaptive response in mice, we have learned that the retina responds to low and high dose gamma radiation by elevating antioxidant-related genes at early time points (4hrs) and that this response returns to control levels after 1 day post-irradiation. We are expanding this research with another collaborative study that investigates the combined effects of radiation exposure and iron overload on sensitivity to radiation injury in rat eyes. All main eye structures will be analyzed in this study: retina, lens and cornea. A study in collaboration with the Space Human Factors and Habitability Element (SHFH) investigates the effects of lunar dust exposure on the rat cornea. It is anticipated that common underlying oxidative stress mechanisms of damage may be observed as a result of these three stressors: radiation, nutritional iron and lunar dust. The contribution of fluid shift is addressed by a study using rats subjected to hindlimb suspension. The hypothesis to be tested in this study is that the mechanical stress imparted by the pressure differential across the optic disc and lamina cribosa will impact oxygenation (therefore causing oxidative stress and hypoxia) and cell survival. This study also includes the assessment of two nutritional antioxidant countermeasures: epigallocatechin gallate (green tea) and resveratrol. Finally, as a result of two successful tissue sharing efforts, we are proceeding with the analysis of eye samples of mice aboard two shuttle missions: STS-133 and STS-135. Results from the STS-133 study are presented in an independent abstract. Briefly, the results show that spaceflight represents a source of environmental stress that directly translates into oxidative and cellular stress in the retina. Similar analysis is also planned for the cornea. These samples add large value to our current vision research as they provide data on the direct effects of low-earth orbit spaceflight on eye structures and physiology.

Zanello, Susana B.↗

NASA NTRS2003

Bit-Serial Adder Based on Quantum Dots

A proposed integrated circuit based on quantum-dot cellular automata (QCA) would function as a bit-serial adder. This circuit would serve as a prototype building block for demonstrating the feasibility of quantum-dots computing and for the further development of increasingly complex and increasingly capable quantum-dots computing circuits. QCA-based bit-serial adders would be especially useful in that they would enable the development of highly parallel and systolic processors for implementing fast Fourier, cosine, Hartley, and wavelet transforms. The proposed circuit would complement the QCA-based circuits described in "Implementing Permutation Matrices by Use of Quantum Dots" (NPO-20801), NASA Tech Briefs, Vol. 25, No. 10 (October 2001), page 42 and "Compact Interconnection Networks Based on Quantum Dots" (NPO-20855), which appears elsewhere in this issue. Those articles described the limitations of very-large-scale-integrated (VLSI) circuitry and the major potential advantage afforded by QCA. To recapitulate: In a VLSI circuit, signal paths that are required not to interact with each other must not cross in the same plane. In contrast, for reasons too complex to describe in the limited space available for this article, suitably designed and operated QCA-based signal paths that are required not to interact with each other can nevertheless be allowed to cross each other in the same plane without adverse effect. In principle, this characteristic could be exploited to design compact, coplanar, simple (relative to VLSI) QCA-based networks to implement complex, advanced interconnection schemes. To enable a meaningful description of the proposed bit-serial adder, it is necessary to further recapitulate the description of a quantum-dot cellular automation from the first-mentioned prior article: A quantum-dot cellular automaton contains four quantum dots positioned at the corners of a square cell. The cell contains two extra mobile electrons that can tunnel (in the quantum-mechanical sense) between neighboring dots within the cell. The Coulomb repulsion between the two electrons tends to make them occupy antipodal dots in the cell. For an isolated cell, there are two energetically equivalent arrangements (denoted polarization states) of the extra electrons. The cell polarization is used to encode binary information. Because the polarization of a nonisolated cell depends on Coulomb-repulsion interactions with neighboring cells, universal logic gates and binary wires could be constructed, in principle, by arraying QCA of suitable design in suitable patterns. Again, for reasons too complex to describe here, in order to ensure accuracy and timeliness of the output of a QCA array, it is necessary to resort to an adiabatic switching scheme in which the QCA array is divided into subarrays, each controlled by a different phase of a multiphase clock signal. In this scheme, each subarray is given time to perform its computation, then its state is frozen by raising its inter-dot potential barriers and its output is fed as the input to the successor subarray. The successor subarray is kept in an unpolarized state so it does not influence the calculation of preceding subarray. Such a clocking scheme is consistent with pipeline computation in the sense that each different subarray can perform a different part of an overall computation. In other words, QCA arrays are inherently suitable for pipeline and, moreover, systolic computations. This sequential or pipeline aspect of QCA would be utilized in the proposed bit-serial adders.

Fijany, Amir↗

NASA NTRS2012

A Multiscale Computational Model of the Response of Swine Epidermis After Acute Irradiation

Radiation exposure from Solar Particle Events can lead to very high skin dose for astronauts on exploration missions outside the protection of the Earth s magnetic field [1]. Assessing the detrimental effects to human skin under such adverse conditions could be predicted by conducting territorial experiments on animal models. In this study we apply a computational approach to simulate the experimental data of the radiation response of swine epidermis, which is closely similar to human epidermis [2]. Incorporating experimentally measured histological and cell kinetic parameters into a multiscale tissue modeling framework, we obtain results of population kinetics and proliferation index comparable to unirradiated and acutely irradiated swine experiments [3]. It is noted the basal cell doubling time is 10 to 16 days in the intact population, but drops to 13.6 hr in the regenerating populations surviving irradiation. This complex 30-fold variation is proposed to be attributed to the shortening of the G1 phase duration. We investigate this radiation induced effect by considering at the sub-cellular level the expression and signaling of TGF-beta, as it is recognized as a key regulatory factor of tissue formation and wound healing [4]. This integrated model will allow us to test the validity of various basic biological rules at the cellular level and sub-cellular mechanisms by qualitatively comparing simulation results with published research, and should lead to a fuller understanding of the pathophysiological effects of ionizing radiation on the skin.

FROM↗

NASA NTRS2012

Reproducing the Photospheric Magnetic Field Evolution during the Rise of Cycle 24 with Flux Transport by Supergranules

We simulate the transport of magnetic flux in the Sun s photosphere by an evolving pattern of cellular horizontal flows (supergranules). Characteristics of the simulated flow pattern can match observed characteristics including the velocity power spectrum, cell lifetimes, and cell motions in longitude and latitude. Simulations using an average, and north-south symmetric, meridional motion of the cellular pattern produce polar magnetic fields that are too weak in the North and too strong in the South. Simulations using cellular patterns with meridional motions that evolve with the observed changes in strength and north-south asymmetry will be analyzed to see if they reproduce the polar field evolution observed during the rise of Cycle 24.

Hathaway, David↗

NASA NTRS2012

Reproducing the Photospheric Magnetic Field Evolution During the Rise of Cycle 24 with Flux Transport by Supergranules

We simulate the transport of magnetic flux in the Sun s photosphere by an evolving pattern of cellular horizontal flows (supergranules). Characteristics of the simulated flow pattern match observed characteristics including the velocity power spectrum, cell lifetimes, and cell pattern motion in longitude and latitude. Simulations using an average, and north-south symmetric, meridional motion of the cellular pattern produce polar magnetic fields that are too weak in the North and too strong in the South. Simulations using cellular patterns with meridional motions that evolve with the observed changes in strength and north-south asymmetry will be analyzed to see if they reproduce the polar field evolution observed during the rise of Cycle 24.

Hathaway, David H.↗

NASA NTRS2014

Methods and Devices for Micro-Isolation, Extraction, and/or Analysis of Microscale Components

Provided herein are devices and methods for the micro-isolation of biological cellular material. A micro-isolation apparatus described can comprise a photomask that protects regions of interest against DNA-destroying illumination. The micro-isolation apparatus can further comprise photosensitive material defining access wells following illumination and subsequent developing of the photosensitive material. The micro-isolation apparatus can further comprise a chambered microfluidic device comprising channels providing access to wells defined in photosensitive material. The micro-isolation apparatus can comprise a chambered microfluidic device without access wells defined in photosensitive material where valves control the flow of gases or liquids through the channels of the microfluidic device. Also included are methods for selectively isolating cellular material using the apparatuses described herein, as are methods for biochemical analysis of individual regions of interest of cellular material using the devices described herein. Further included are methods of making masking arrays useful for the methods described herein.

Kartalov, Emil P.↗

NASA NTRS2013

Lab-On-Chip Clinorotation System for Live-Cell Microscopy Under Simulated Microgravity

Cells in microgravity are subject to mechanical unloading and changes to the surrounding chemical environment. How these factors jointly influence cellular function is not well understood. We can investigate their role using ground-based analogues to spaceflight, where mechanical unloading is simulated through the time-averaged nullification of gravity. The prevailing method for cellular microgravity simulation is to use fluid-filled containers called clinostats. However, conventional clinostats are not designed for temporally tracking cell response, nor are they able to establish dynamic fluid environments. To address these needs, we developed a Clinorotation Time-lapse Microscopy (CTM) system that accommodates lab-on- chip cell culture devices for visualizing time-dependent alterations to cellular behavior. For the purpose of demonstrating CTM, we present preliminary results showing time-dependent differences in cell area between human mesenchymal stem cells (hMSCs) under modeled microgravity and normal gravity.

Yew, Alvin G.↗

NASA NTRS2015

Determination of Roles of Microgravity and Ionizing Radiation on the Reactivation of Epstein-Barr Virus In Vitro

Astronauts experience symptomatic and asymptomatic herpes virus reactivation during spaceflight. We have shown increases in reactivation of Epstein-Barr virus (EBV), cytomegalovirus (CMV) and varicella zoster virus (VZV) and shedding in body fluids (saliva and urine) in astronauts during space travel. Alterations in immunity, increased stress hormone levels, microgravity, increased radiation, and other conditions unique to spaceflight may promote reactivation of latent herpes viruses. Unique mechanico-physico forces associated with spaceflight can have profound effects on cellular function, especially immune cells. In space flight analog studies such as Antarctica, bed rest studies, and NASA's undersea habitat (Aquarius), reactivation of these viruses occurred, but to a lesser extent than spaceflight. Spaceflight analogs model some spaceflight factors, but none of the analogs recreates all factors experienced in space. Most notably, microgravity and radiation are not included in many analogs. Stress, processed through the HPA axis and SAM systems, induces viral reactivation. However, the respective roles of microgravity and increased space radiation levels or if any synergy exists are not known. Therefore, we studied the effect of modeled space radiation and/or microgravity, independent of the immune system on the changes in cellular gene expression that results in viral (EBV) reactivation. The effects of modeled microgravity and low shear on EBV replication and cellular and EBV gene expression were studied in human B-lymphocyte cell cultures. Latently infected B-lymphocytes were propagated in the rotating wall bioreactor and irradiated with the various dosages of gamma irradiation. At specific time intervals following exposure to modeled microgravity, the cells and supernatant were harvested and reactivation of EBV were assessed by measuring EBV and gene expression, DNA methylation, and infectious virus production.

Mehta, Satish K↗

NASA NTRS2016

The Use of Microgravity Simulators for Space Research

The spaceflight environment is known to influence biological processes ranging from stimulation of cellular metabolism to possible impacts on cellular damage repair, suppression of immune functions, and bone loss in astronauts. Microgravity is one of the most significant stress factors experienced by living organisms during spaceflight, and therefore, understanding cellular responses to altered gravity at the physiological and molecular level is critical for expanding our knowledge of life in space. Since opportunities to conduct experiments in space are scarce, various microgravity simulators and analogues have been widely used in space biology ground studies. Even though simulated microgravity conditions have produced some, but not all of the biological effects observed in the true microgravity environment, they provide test beds that are effective, affordable, and readily available to facilitate microgravity research. A Micro-g Simulator Center is being developed at Kennedy Space Center (KSC) to offer a variety of microgravity simulators and platforms for Space Biology investigators. Assistance will be provided by both KSC and external experts in molecular biology, microgravity simulation, and engineering. Comparisons between the physical differences in microgravity simulators, examples of experiments using the simulators, and scientific questions regarding the use of microgravity simulators will be discussed.

Simulation↗

NASA NTRS1980

Lab-On-Chip Clinorotation System for Live-Cell Microscopy Under Simulated Microgravity

Yew, Alvin G.↗

NASA NTRS2016

The Use of Microgravity Simulators for Space Research

The spaceflight environment is known to influence biological processes ranging from stimulation of cellular metabolism to possible impacts on cellular damage repair, suppression of immune functions, and bone loss in astronauts. Microgravity is one of the most significant stress factors experienced by living organisms during spaceflight, and therefore, understanding cellular responses to altered gravity at the physiological and molecular level is critical for expanding our knowledge of life in space. Since opportunities to conduct experiments in space are scarce, various microgravity simulators and analogues have been widely used in space biology ground studies. Even though simulated microgravity conditions have produced some, but not all of the biological effects observed in the true microgravity environment, they provide test beds that are effective, affordable, and readily available to facilitate microgravity research. Kennedy Space Center (KSC) provides ground microgravity simulator support to offer a variety of microgravity simulators and platforms for Space Biology investigators. Assistance will be provided by both KSC and external experts in molecular biology, microgravity simulation, and engineering. Comparisons between the physical differences in microgravity simulators, examples of experiments using the simulators, and scientific questions regarding the use of microgravity simulators will be discussed.

Simulation↗

NASA NTRS2018

UV-Resistant Microbes and UV-Blocking Microbial Extract

The present disclosure relates to a composition including an extract from an Acidithiobacillus bacteria or a yeast extracted after exposure of the bacteria to UV radiation. The disclosure further relates to a method of preparing a UV-blocking composition by exposing a culture of Acidithiobacillus or yeast to UV radiation and extracting UV-blocking cellular material produced in response to the UV radiation from the Acidithiobacillus or yeast. The disclosure further relates to a method of protecting an item from UV radiation damage by extracting UV-blocking cellular material from Acidithiobacillus or yeast exposed to UV radiation and covering the item with the UV-blocking cellular material. The disclosure further relates to a UV-resistant yeast cell and a UV-resistant bacterial cell.

Cuero, Raul G.↗

NASA NTRSDate not supplied

Hazards of Lunar Surface Exploration: Determining the Immunogenicity/Allergenicity of Lunar Dust

There are multiple Apollo program reports of lunar dust (LD) exposure leading to significant upper respiratory symptoms in select crewmembers. Possible mechanisms include particulate irritation, oxidization and release of noxious gas, or legitimate adaptive immune-mediated response. Although sterile non-protein matter would not be expected to be an allergen, one Apollo flight surgeon reported increasing symptoms upon repeated exposure, with associated eosinophilia indicative of allergy (*Acta Astronautica. 2008 63 (7–10): 980–987). Many ISS crews display a pattern of persistent immune system dysregulation and latent virus reactivation (NPJ Microgravity. 2015 Sep 3; 1:15013; NPJ Microgravity. 2017 Apr 12; 3:11). Some ISS crews manifest atypical respiratory and/or dermatitis symptoms which could have an allergic pathogenesis (J Allergy Clin. Immunol. Pract. 2016 Jul-Aug; 4(4):759-762.e8). It is logical to anticipate crew immune dysregulation would worsen during prolonged deep space missions. Planetary surface hazards will only complicate crew health risks. This study hypothesizes that LD exposure can alter susceptible individuals’ immune responses such that repeated exposure will elicit an IgE mediated allergic response either to the LD itself or concomitant antigen exposure during spaceflight. This will adversely increase clinical and operational impacts for long-duration lunar astronauts and affect countermeasure requirements for surface vehicles. Specific aims for this study are (1) Does in vitro LD exposure result in increased histamine from human peripheral blood basophils? (2) Can LD impact the capacity of CD4+ helper and/or CD19+ B-cell mediated IgE production? To address these questions, a set of in-vitro cell culture experiments will be employed (short and long term) using human peripheral blood mononuclear cells (PBMC) and basophils from both atopic and non-atopic individuals, as well as established human basophil and mast cell lines. Cells will be co-cultured with cellular mitogens, common recall antigens (tetanus, Der p1), nickel (as a possible allergenic component of LD), with or without graded amounts of LD, to study whether LD exposure for varying time intervals will alter the generation of selective immune responses associated with clinical allergic reactions. Measured outputs include supernatant-derived IgE, tryptase, histamine and selected cytokine levels. Cellular activation will be monitored by assessing activation markers via flow cytometry. EM/x-ray analysis will be used to determine cellular interactions with dust particles. The minimal amount of LD (Apollo 14 dust) and controls/simulants have been requested. This study, originally planned as an FY20/21 activity, was delayed due to the COVID pandemic. It is now scheduled to be performed during FY22.

Brian Crucian↗

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↗