Proceedings of the National Academy of Sciences of the United States of America
1091-6490
0027-8424
Mỹ
Cơ quản chủ quản: NATL ACAD SCIENCES , National Academy of Sciences
Lĩnh vực:
Multidisciplinary
Phân tích ảnh hưởng
Thông tin về tạp chí
PNAS publishes research reports, Brief Reports, Letters, Front Matter magazine content, Commentaries, Perspectives, and Colloquium Papers. In accordance with the guiding principles established by George Ellery Hale in 1914, PNAS also publishes brief first announcements of NAS members' and foreign associates' more important contributions to research and of work that appears to a member to be of particular importance. All submissions are evaluated by a member of the Editorial Board prior to acceptance. PNAS is a general science journal, and all papers should be intelligible to a broad scientific audience.
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Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone Treatment with isolated allogeneic mesenchymal cells has the potential to enhance the therapeutic effects of conventional bone marrow transplantation in patients with genetic disorders affecting mesenchymal tissues, including bone, cartilage, and muscle. To demonstrate the feasibility of mesenchymal cell therapy and to gain insight into the transplant biology of these cells, we used gene-marked, donor marrow-derived mesenchymal cells to treat six children who had undergone standard bone marrow transplantation for severe osteogenesis imperfecta. Each child received two infusions of the allogeneic cells. Five of six patients showed engraftment in one or more sites, including bone, skin, and marrow stroma, and had an acceleration of growth velocity during the first 6 mo postinfusion. This improvement ranged from 60% to 94% (median, 70%) of the predicted median values for age- and sex-matched unaffected children, compared with 0% to 40% (median, 20%) over the 6 mo immediately preceding the infusions. There was no clinically significant toxicity except for an urticarial rash in one patient just after the second infusion. Failure to detect engraftment of cells expressing the neomycin phosphotransferase marker gene suggested the potential for immune attack against therapeutic cells expressing a foreign protein. Thus, allogeneic mesenchymal cells offer feasible posttransplantation therapy for osteogenesis imperfecta and likely other disorders originating in mesenchymal precursors.
Tập 99 Số 13 - Trang 8932-8937 - 2002
Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains Stem cells are a valuable resource for treating disease, but limited access to stem cells from tissues such as brain restricts their utility. Here, we injected marrow stromal cells (MSCs) into the lateral ventricle of neonatal mice and asked whether these multipotential mesenchymal progenitors from bone marrow can adopt neural cell fates when exposed to the brain microenvironment. By 12 days postinjection, MSCs migrated throughout the forebrain and cerebellum without disruption to the host brain architecture. Some MSCs within the striatum and the molecular layer of the hippocampus expressed glial fibrillary acidic protein and, therefore, differentiated into mature astrocytes. MSCs also populated neuron rich regions including the Islands of Calleja, the olfactory bulb, and the internal granular layer of the cerebellum. A large number of MSCs also were found within the external granular layer of the cerebellum. In addition, neurofilament positive donor cells were found within the reticular formation of the brain stem, suggesting that MSCs also may have differentiated into neurons. Therefore, MSCs are capable of producing differentiated progeny of a different dermal origin after implantation into neonatal mouse brains. These results suggest that MSCs are potentially useful as vectors for treating a variety of central nervous system disorders.
Tập 96 Số 19 - Trang 10711-10716 - 1999
Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity
The mechanism(s) underlying cardiac reparative effects of bone marrow-derived mesenchymal stem cells (MSC) remain highly controversial. Here we tested the hypothesis that MSCs regenerate chronically infarcted myocardium through mechanisms comprising long-term engraftment and trilineage differentiation. Twelve weeks after myocardial infarction, female swine received catheter-based transendocardial injections of either placebo (
n
= 4) or male allogeneic MSCs (200 million;
n
= 6). Animals underwent serial cardiac magnetic resonance imaging, and in vivo cell fate was determined by co-localization of Y-chromosome (Y
pos
) cells with markers of cardiac, vascular muscle, and endothelial lineages. MSCs engrafted in infarct and border zones and differentiated into cardiomyocytes as ascertained by co-localization with GATA-4, Nkx2.5, and α-sarcomeric actin. In addition, Y
pos
MSCs exhibited vascular smooth muscle and endothelial cell differentiation, contributing to large and small vessel formation. Infarct size was reduced from 19.3 ± 1.7% to 13.9 ± 2.0% (
P
< 0.001), and ejection fraction (EF) increased from 35.0 ± 1.7% to 41.3 ± 2.7% (
P
< 0.05) in MSC but not placebo pigs over 12 weeks. This was accompanied by increases in regional contractility and myocardial blood flow (MBF), particularly in the infarct border zone. Importantly, MSC engraftment correlated with functional recovery in contractility (
R
= 0.85,
P
< 0.05) and MBF (
R
= 0.76,
P
< 0.01). Together these findings demonstrate long-term MSC survival, engraftment, and trilineage differentiation following transplantation into chronically scarred myocardium. MSCs are an adult stem cell with the capacity for cardiomyogenesis and vasculogenesis which contribute, at least in part, to their ability to repair chronically scarred myocardium.
Tập 106 Số 33 - Trang 14022-14027 - 2009
Bone marrow stromal cells use TGF-β to suppress allergic responses in a mouse model of ragweed-induced asthma Bone marrow stromal cells [BMSCs; also known as mesenchymal stem cells (MSCs)] effectively suppress inflammatory responses in acute graft-versus-host disease in humans and in a number of disease models in mice. Many of the studies concluded that BMSC-driven immunomodulation is mediated by the suppression of proinflammatory Th1 responses while rebalancing the Th1/Th2 ratio toward Th2. In this study, using a ragweed induced mouse asthma model, we studied if BMSCs could be beneficial in an allergic, Th2-dominant environment. When BMSCs were injected i.v. at the time of the antigen challenge, they protected the animals from the majority of asthma-specific pathological changes, including inhibition of eosinophil infiltration and excess mucus production in the lung, decreased levels of Th2 cytokines (IL-4, IL-5, and IL-13) in bronchial lavage, and lowered serum levels of Th2 immunoglobulins (IgG1 and IgE). To explore the mechanism of the effect we used BMSCs isolated from a variety of knockout mice, performed in vivo blocking of cytokines and studied the effect of asthmatic serum and bronchoalveolar lavage from ragweed challenged animals on the BMSCs in vitro. Our results suggest that IL-4 and/or IL-13 activate the STAT6 pathway in the BMSCs resulting in an increase of their TGF-β production, which seems to mediate the beneficial effect, either alone, or together with regulatory T cells, some of which might be recruited by the BMSCs. These data suggest that, in addition to focusing on graft-versus-host disease and autoimmune diseases, allergic conditions—specifically therapy resistant asthma—might also be a likely target of the recently discovered cellular therapy approach using BMSCs.
Tập 107 Số 12 - Trang 5652-5657 - 2010
Assessment of therapeutic efficacy and fate of engineered human mesenchymal stem cells for cancer therapy The poor prognosis of patients with aggressive and invasive cancers combined with toxic effects and short half-life of currently available treatments necessitate development of more effective tumor selective therapies. Mesenchymal stem cells (MSCs) are emerging as novel cell-based delivery agents; however, a thorough investigation addressing their therapeutic potential and fate in different cancer models is lacking. In this study, we explored the engineering potential, fate, and therapeutic efficacy of human MSCs in a highly malignant and invasive model of glioblastoma. We show that engineered MSC retain their “stem-like” properties, survive longer in mice with gliomas than in the normal brain, and migrate extensively toward gliomas. We also show that MSCs are resistant to the cytokine tumor necrosis factor apoptosis ligand (TRAIL) and, when engineered to express secreted recombinant TRAIL, induce caspase-mediated apoptosis in established glioma cell lines as well as CD133-positive primary glioma cells in vitro. Using highly malignant and invasive human glioma models and employing real-time imaging with correlative neuropathology, we demonstrate that MSC-delivered recombinant TRAIL has profound anti-tumor effects in vivo. This study demonstrates the efficacy of diagnostic and therapeutic MSC in preclinical glioma models and forms the basis for developing stem cell-based therapies for different cancers.
Tập 106 Số 12 - Trang 4822-4827 - 2009
Mobilized bone marrow cells repair the infarcted heart, improving function and survival
Attempts to repair myocardial infarcts by transplanting cardiomyocytes or skeletal myoblasts have failed to reconstitute healthy myocardium and coronary vessels integrated structurally and functionally with the remaining viable portion of the ventricular wall. The recently discovered growth and transdifferentiation potential of primitive bone marrow cells (BMC) prompted us, in an earlier study, to inject in the border zone of acute infarcts Lin
−
c-
kit
POS
BMC from syngeneic animals. These BMC differentiated into myocytes and vascular structures, ameliorating the function of the infarcted heart. Two critical determinants seem to be required for the transdifferentiation of primitive BMC: tissue damage and a high level of pluripotent cells. On this basis, we hypothesized here that BMC, mobilized by stem cell factor and granulocyte-colony stimulating factor, would home to the infarcted region, replicate, differentiate, and ultimately promote myocardial repair. We report that, in the presence of an acute myocardial infarct, cytokine-mediated translocation of BMC resulted in a significant degree of tissue regeneration 27 days later. Cytokine-induced cardiac repair decreased mortality by 68%, infarct size by 40%, cavitary dilation by 26%, and diastolic stress by 70%. Ejection fraction progressively increased and hemodynamics significantly improved as a consequence of the formation of 15 × 10
6
new myocytes with arterioles and capillaries connected with the circulation of the unaffected ventricle. In conclusion, mobilization of primitive BMC by cytokines might offer a noninvasive therapeutic strategy for the regeneration of the myocardium lost as a result of ischemic heart disease and, perhaps, other forms of cardiac pathology.
Tập 98 Số 18 - Trang 10344-10349 - 2001
PixE promotes dark oligomerization of the BLUF photoreceptor PixD
Cyanobacteria perceive and move (phototax) in response to blue light. In this study, we demonstrate that the PixD blue light-sensing using FAD (BLUF) photoreceptor that governs this response undergoes changes in oligomerization state upon illumination. Under dark conditions we observed that PixD forms a large molecular weight complex with another protein called PixE. Stoicheometric analyses, coupled with sedimentation equilibrium and size exclusion chromatography, demonstrates that PixE drives aggregation of PixD dimers into a stable PixD
10
—PixE
5
complex under dark conditions. Illumination of a flavin chromophore in PixD destabilizes the PixD
10
–PixE
5
complex into monomers of PixE and dimers of PixD. A crystallographic structure of PixD, coupled with Gibbs free energy calculation between interacting faces of PixD, lends to a model in which a light induces a conformational change in a critical PixD-interfacing loop that results in destabilization of the PixD
10
–PixE
5
complex.
Tập 105 Số 33 - Trang 11715-11719 - 2008
Diffractive optics-based heterodyne-detected four-wave mixing signals of protein motion: From “protein quakes” to ligand escape for myoglobin Ligand transport through myoglobin (Mb) has been observed by using
optically heterodyne-detected transient grating spectroscopy.
Experimental implementation using diffractive optics has provided
unprecedented sensitivity for the study of protein motions by enabling
the passive phase locking of the four beams that constitute the
experiment, and an unambiguous separation of the Real and Imaginary
parts of the signal. Ligand photodissociation of carboxymyoglobin
(MbCO) induces a sequence of events involving the relaxation of the
protein structure to accommodate ligand escape. These motions show up
in the Real part of the signal. The ligand (CO) transport process
involves an initial, small amplitude, change in volume, reflecting the
transit time of the ligand through the protein, followed by a
significantly larger volume change with ligand escape to the
surrounding water. The latter process is well described by a single
exponential process of 725 ± 15 ns at room temperature. The
overall dynamics provide a distinctive signature that can be understood
in the context of segmental protein fluctuations that aid ligand escape
via a few specific cavities, and they suggest the existence of discrete
escape pathways.
Tập 98 Số 11 - Trang 6110-6115 - 2001
Ligand-activated site-specific recombination in mice. Current mouse gene targeting technology is unable to introduce somatic mutations at a chosen time and/or in a given tissue. We report here that conditional site-specific recombination can be achieved in mice using a new version of the Cre/lox system. The Cre recombinase has been fused to a mutated ligand-binding domain of the human estrogen receptor (ER) resulting in a tamoxifen-dependent Cre recombinase, Cre-ERT, which is activated by tamoxifen, but not by estradiol. Transgenic mice were generated expressing Cre-ERT under the control of a cytomegalovirus promoter. We show that excision of a chromosomally integrated gene flanked by loxP sites can be induced by administration of tamoxifen to these transgenic mice, whereas no excision could be detected in untreated animals. This conditional site-specific recombination system should allow the analysis of knockout phenotypes that cannot be addressed by conventional gene targeting.
Tập 93 Số 20 - Trang 10887-10890 - 1996
Natural capital and ecosystem services informing decisions: From promise to practice
The central challenge of the 21st century is to develop economic, social, and governance systems capable of ending poverty and achieving sustainable levels of population and consumption while securing the life-support systems underpinning current and future human well-being. Essential to meeting this challenge is the incorporation of natural capital and the ecosystem services it provides into decision-making. We explore progress and crucial gaps at this frontier, reflecting upon the 10 y since the Millennium Ecosystem Assessment. We focus on three key dimensions of progress and ongoing challenges: raising awareness of the interdependence of ecosystems and human well-being, advancing the fundamental interdisciplinary science of ecosystem services, and implementing this science in decisions to restore natural capital and use it sustainably. Awareness of human dependence on nature is at an all-time high, the science of ecosystem services is rapidly advancing, and talk of natural capital is now common from governments to corporate boardrooms. However, successful implementation is still in early stages. We explore why ecosystem service information has yet to fundamentally change decision-making and suggest a path forward that emphasizes: (
i
) developing solid evidence linking decisions to impacts on natural capital and ecosystem services, and then to human well-being; (
ii
) working closely with leaders in government, business, and civil society to develop the knowledge, tools, and practices necessary to integrate natural capital and ecosystem services into everyday decision-making; and (
iii
) reforming institutions to change policy and practices to better align private short-term goals with societal long-term goals.
Tập 112 Số 24 - Trang 7348-7355 - 2015