Epistemic_Statements  

CORD-19:0376103fd7863b10e41a0f59fe226be9765f34c7 JSONTXT 9 Projects

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Id Subject Object Predicate Lexical cue
T1 639-746 Epistemic_statement denotes Recent evidence suggests that BPD may have long-term respiratory complications that reach beyond childhood.
T2 747-1021 Epistemic_statement denotes Numerous follow-up studies indicate that children and young adults who were born very preterm are at an increased risk of respiratory symptoms, poor lung function, and lower exercise capacity [3] [4] [5] [6] [7] this is especially apparent in infants who have developed BPD.
T3 1228-1519 Epistemic_statement denotes 10 Progress toward decreasing the incidence/severity of BPD over the next few years using currently available techniques and strategies is likely (ie, optimization of antenatal management combined with surfactant and early noninvasive ventilatory support targeting lower oxygen saturations).
T4 1520-1751 Epistemic_statement denotes 11 However, further understanding of the mechanisms involved in lung development, injury, and repair are necessary to advance toward preventing lung injury and/or promoting lung development/regeneration in prematurely born infants.
T5 1752-1913 Epistemic_statement denotes Exciting discoveries in stem cell biology in recent years may offer new insight into the pathogenesis of BPD and, more importantly, open new therapeutic avenues.
T6 1914-2058 Epistemic_statement denotes Stem cells are primitive cells capable of extensive self-renewal with the potential to give rise to multiple differentiated cellular phenotypes.
T7 2059-2233 Epistemic_statement denotes 12 These cells are not only critical for organogenesis and growth during the early stages of development but also contribute to organ repair and regeneration throughout life.
T8 2234-2346 Epistemic_statement denotes The concept of developmental potency refers to the range of possible fates open to cells during differentiation.
T9 2772-3047 Epistemic_statement denotes By contrast, somatic stem cells (also termed adult stem cells [ASCs] ) are cells that have assumed increasing degrees of fate restriction and are either multipotent (ie, can differentiate into a limited range of cell types) or unipotent (ie, can generate only one cell type).
T10 3048-3285 Epistemic_statement denotes 13 Residual pools of such multipotent or unipotent stem cells are hypothesized to reside in almost all adult organs, and have the ability to contribute to tissue repair and regeneration via repopulation during growth, injury, or disease.
T11 3659-3825 Epistemic_statement denotes 14 By contrast, anatomically complex tissues that turn over more slowly (ie, brain, heart, lung, and kidney) do not appear to support a classical stem cell hierarchy.
T12 3826-4027 Epistemic_statement denotes Such tissues are thought to be maintained by stem/progenitor cell populations that are organized in a nonclassical hierarchy and are recruited in a facultative manner for regeneration following injury.
T13 4225-4468 Epistemic_statement denotes 15 Recent research suggests that the adult lung harbors rare populations of multipotent epithelial stem cells that are regulated by specific microenvironmental cellular niches, and are putatively recruited to repopulate the damaged epithelium.
T14 4630-4725 Epistemic_statement denotes Lungs are complex organs constituted by more than 40 cell types derived from all 3 germ layers.
T15 4960-5135 Epistemic_statement denotes 21 At present, the localization and properties of lung stem/progenitor cell niches and the type of cells within each niche are of major interest, yet also present controversy.
T16 5136-5301 Epistemic_statement denotes Complexity of the lung architecture combined with an extensive diversity of cell types and niches has hindered the identification of true lung stem/progenitor cells.
T17 5590-5762 Epistemic_statement denotes 22 In doing so, it has been observed that relatively differentiated airway and alveolar epithelial cell types are capable of proliferating in response to epithelial injury.
T18 5763-5961 Epistemic_statement denotes 15 This observation has drawn the focus of lung stem/progenitor cell research into identifying and defining those epithelial cell subpopulations that appear to contribute to postinjury regeneration.
T19 6474-6632 Epistemic_statement denotes While stem/progenitor cells in the proximal airways have been explored more extensively, the study of distal stem/progenitor cells remains more controversial.
T20 6765-6900 Epistemic_statement denotes 24 Studies have indicated that SMGs may serve as a protective niche for adult epithelial stem/progenitor cells of the proximal airways.
T21 7451-7739 Epistemic_statement denotes 26 An additional niche of stem/progenitor cells in the proximal airway is the K14expressing tracheobronchial basal cells, which have been shown to repopulate the denuded airway epithelium, including columnar secretory and ciliated cells, following naphthalene-induced epithelial ablation.
T22 7740-7867 Epistemic_statement denotes 27 This finding indicates that the K14expressing basal cells are implicated as a stem/progenitor cell for this airway location.
T23 7868-7959 Epistemic_statement denotes The potential contribution of these cells to the repair of the distal lung remains unknown.
T24 7960-8145 Epistemic_statement denotes With transition from the proximal to distal airways, it can be seen that the notion of multiple niches supporting different populations and their progenitors within the lung is evident.
T25 8146-8315 Epistemic_statement denotes This idea is supported by studies using naphthalene to deplete the airways of Clara cells, revealing a subset of Clara cells that are CCSP 1 , yet naphthalene resistant.
T26 8556-8729 Epistemic_statement denotes 28, 29 More recently, Volckaert and colleagues 30 also proposed that parabronchial smooth muscle cells (PSMCs) constitute a stem/progenitor cell niche for the Clara V cells.
T27 9332-9491 Epistemic_statement denotes However, based on the techniques used, there has been some ambiguity regarding the lineage potential 23, 31 and contribution of these cells to alveolar repair.
T28 9492-9775 Epistemic_statement denotes 32 McQualter and colleagues 18 used a multiparameter cell separation strategy and an organotypic in vitro clonogenic assay to detect and characterize a rare population of multipotent adult lung epithelial stem cells that give rise to airway and alveolar epithelial lineages in vitro.
T29 10638-10769 Epistemic_statement denotes Gene-expression profiles of these pods suggest that they are intermediates in the reconstitution of the alveolar-capillary network.
T30 11136-11330 Epistemic_statement denotes 34, 35 Since then, type-II pneumocytes have been speculated to contain a subpopulation of progenitors cells that can undergo reactivation into a progenitor-like state in response to injury cues.
T31 12165-12416 Epistemic_statement denotes 21 Current knowledge of lung mesenchymal precursors is limited; however, there is evidence that small populations of resident lung cells expressing certain phenotypic characteristics of mesenchymal cells with progenitor capacity exist within the lung.
T32 12417-12590 Epistemic_statement denotes Resident lung "side population" (SP) cells, which appear to have both mesenchymal and epithelial potential, have been isolated based on their capacity to efflux Hoechst dye.
T33 12792-12986 Epistemic_statement denotes 40 Although it has been demonstrated that these SP cells are a source of adult lung mesenchymal stem cells (MSCs), 39 the role of SP cells in endogenous lung repair is not completely understood.
T34 12987-13208 Epistemic_statement denotes Furthermore, McQualter and colleagues 41 described a population of endogenous fibroblastic progenitor cells with clonogenic potential in the adult lung, which are predominantly representative of mesenchymal cell lineages.
T35 13209-13485 Epistemic_statement denotes The cell fraction defined by McQualter and colleagues 18 was of similar cell phenotype (CD45 À , CD31 À , Sca-1 1 , CD43 1 ) to the cell fraction defined as BASCs; however, they coexpressed immunophenotypic markers definitive of lung fibroblastic rather than epithelial cells.
T36 13486-13656 Epistemic_statement denotes 41 These findings highlight the need for alternative, specific markers to enable precise identification of endogenous stem/progenitor cell subpopulations within the lung.
T37 13915-14078 Epistemic_statement denotes 42 Experimental evidence indicates that the injured lung stimulates the release and preferential homing of MSCs, a population of ASCs derived from the bone marrow.
T38 14079-14240 Epistemic_statement denotes 43, 44 However, the mechanism by which exogenous progenitors, such as bone marrow MSCs, assume lung phenotype remains unclear, as does its clinical significance.
T39 14241-14451 Epistemic_statement denotes 45, 46 Lung Endothelial Progenitor Cells Endothelial progenitor cells (EPCs), a population of vascular precursor cells, have also recently received attention in the context of lung development and regeneration.
T40 14452-14662 Epistemic_statement denotes Indeed, given the importance of lung angiogenesis and vascular growth factors during lung growth and repair, vascular progenitor cells are appealing candidate cells likely to be involved in the same mechanisms.
T41 15219-15370 Epistemic_statement denotes It has been demonstrated that both circulating and resident lung EPCs are likely to contribute to endothelial cell regeneration and repair in the lung.
T42 15600-15739 Epistemic_statement denotes Indeed, several major lung diseases likely involve dysregulation in the numbers and/or the function of resident lung stem/progenitor cells.
T43 15740-15955 Epistemic_statement denotes 46 For instance, depletion or functional impairment of alveolar epithelial and/or EPCs could putatively underlie the pathogenesis of alveolar growth arrest or destruction observed in BPD and emphysema, respectively.
T44 15956-16104 Epistemic_statement denotes In such a scenario, augmentation of stem cells is an appealing strategy to minimize lung injury, promote repair, or possibly regenerate lost tissue.
T45 16105-16292 Epistemic_statement denotes Recent animal and human studies suggest that damage or depletion of epithelial and/ or vascular stem/progenitor cells in the developing lung likely contributes to the pathogenesis of BPD.
T46 16419-16547 Epistemic_statement denotes Irwin and colleagues 51 showed a reduction in the number and endothelial differentiation potential of multipotent lung SP cells.
T47 16725-16848 Epistemic_statement denotes 52 This finding highlights the potential of stem cell supplementation for the prevention or repair of neonatal lung injury.
T48 17630-17811 Epistemic_statement denotes 55 Furthermore, these cells were shown to acquire a myofibroblast phenotype, which suggest that they could contribute to the profibrotic changes and arrested alveolarization in BPD.
T49 17812-18097 Epistemic_statement denotes 56 However, in contrast to tracheal aspirate MSCs, human bone marrow-derived MSCs did not Stem Cells and Bronchopulmonary Dysplasia undergo myofibroblastic differentiation in response to transforming growth factor b1, suggesting distinct properties between these 2 populations of MSCs.
T50 18098-18320 Epistemic_statement denotes 56 Indeed, it is possible that these reported resident lung MSCs are perturbed in BPD, as their cell phenotype is not analogous to the endogenous MSCs described by McQualter and colleagues 41 in the absence of lung injury.
T51 18321-18728 Epistemic_statement denotes Therefore, with the growing interest in harnessing the therapeutic effects of stem progenitor cells for neonatal lung injury, it is necessary to perform further thorough investigations to understand the behavior of MSCs from different populations (ie, lung, umbilical cord blood [UCB], bone marrow) in the presence and absence of lung injury, and how this could affect potential cellbased therapies for BPD.
T52 19351-19544 Epistemic_statement denotes In contrast to the findings of Borghesi and colleagues, 59 Paviotti and colleagues 60 recently reported no association between the number of EPCs at birth and the subsequent development of BPD.
T53 19545-19763 Epistemic_statement denotes The apparent discordance between studies reporting EPCs in preterm infants highlights the importance of appropriately defining an EPC and establishing criteria similar to the "minimal criteria" for characterizing MSCs.
T54 19764-19851 Epistemic_statement denotes 61 Furthermore, assessing EPC function may be more revealing than assessing EPC number.
T55 19852-20067 Epistemic_statement denotes These observations suggest that the capacity of resident stem cell populations to undergo self-renewal and regeneration can be limited, because of the natural effect of increasing age and/or the presence of disease.
T56 20068-20286 Epistemic_statement denotes This situation forms the rationale for the therapeutic potential of stem cell-based therapies, either through stimulation of endogenous stem cell pools or their therapeutic replacement with exogenousderived stem cells.
T57 20287-20386 Epistemic_statement denotes Such cell-replacement therapies already show promise in debilitating childhood and adult disorders.
T58 20519-20869 Epistemic_statement denotes Numerous studies in experimental animal models provide compelling evidence for the beneficial effects of stem cell therapy approaches for a wide variety of adult lung diseases ( Table 2) , including acute lung injury/acute respiratory distress syndrome, pulmonary hypertension, asthma, and chronic obstructive pulmonary disease (including emphysema).
T59 20870-21040 Epistemic_statement denotes [65] [66] [67] Of the many different stem/progenitor cell therapies that have been used in experimental models, MSCs appear to be the most extensively examined cell type.
T60 21041-21136 Epistemic_statement denotes MSCs can be sourced from the bone marrow, UCB, Wharton jelly, the placenta, and adipose tissue.
T61 21137-22577 Epistemic_statement denotes 68 As outlined in Table 2 benefits of MSC therapy in experimental adult lung diseases include, but are not limited to, improvements in alveolar, airway, and vascular structure; attenuation of lung inflammation; decreased pulmonary fibrosis; reduced pulmonary edema, hemorrhage, and alveolar and endothelial permeability; and Abbreviations: Ang-1, angiopoietin-1; APN, adiponectin; AT1, alveolar epithelial type 1; AT2, alveolar epithelial type 2; BMC, bone marrow-derived cells; CdM, conditioned media; EGF, epidermal growth factor; eNOS, endothelial nitric oxide synthase; EPC, endothelial progenitor cell; HGF, hepatocyte growth factor; HSC, hematopoietic stem cell; hAEC, human amnion epithelial cell; hUC, human umbilical cord; hUCB, human umbilical cord blood; IL, interleukin; i.n., intranasal; i.p., intraperitoneal; iPS, induced pluripotent stem; i.t., intratracheal; i.v., intravenous; KGF, keratinocyte growth factor; LPS, lipopolysaccharide; LVRS, lung volume reduction surgery; MMP-2, matrix metalloproteinase 2; MPO, myeloperoxidase; MSC, mesenchymal stem cell; NF-kB, nuclear factor kappa light-chain enhancer of activated B cells; NO, nitric oxide; PaO 2 , partial pressure of oxygen in arterial blood; PGA, polyglycolic acid; RV, right ventricle; SaO 2 , oxygen saturation; TGF-b, transforming growth factor b; Th2, helper T cell type 2; TIMP, tissue inhibitor of metalloproteinase; VEGF, vascular endothelial growth factor.
T62 22630-22830 Epistemic_statement denotes Of importance, the beneficial therapeutic actions of MSCs appear to be mediated through paracrine mechanisms and immunomodulatory effects, rather than cell engraftment and direct actions in the lungs.
T63 22996-23239 Epistemic_statement denotes Given the perturbations of resident lung stem cells in BPD, the ideal therapeutic approach would involve replenishing the lung with healthy multipotent stem/progenitor cells that repopulate, repair, and regenerate the injured, developing lung.
T64 23240-23381 Epistemic_statement denotes Indeed, several recent studies have demonstrated promising outcomes using different stem/ progenitor cell types in animal models of BPD (Fig.
T65 23748-23944 Epistemic_statement denotes 52, 53, 70, 71 Low engraftment and differentiation of these MSCs into the injured neonatal lung suggest that the potential mechanisms through which MSCs exert their actions are paracrine mediated.
T66 24305-24409 Epistemic_statement denotes 52, 53, 70 Furthermore, the therapeutic benefits of MSC-CdM may surpass those of MSCs, with in vivo Fig.
T67 24525-24752 Epistemic_statement denotes Several studies have demonstrated the effects of stem/progenitor cells and stem/progenitor cell-derived growth factors (ie, conditioned media) to promote lung regeneration following neonatal lung injury in animal models of BPD.
T68 25376-25613 Epistemic_statement denotes Chang and colleagues 73 also show that the route of administration may alter the outcome, with intratracheal transplantation resulting in a more prominent attenuation of hyperoxia-induced lung injury than intraperitoneal transplantation.
T69 25770-25999 Epistemic_statement denotes This study indicated that intratracheal delivery of a minimum of 5 Â 10 4 cells is required to exhibit efficient anti-inflammatory, antifibrotic, and antioxidative effects following hyperoxia-induced lung injury in neonatal rats.
T70 26000-26149 Epistemic_statement denotes 72 In light of these findings, further studies determining the optimal dose of MSCs for potential clinical benefit in human neonates are anticipated.
T71 26150-26279 Epistemic_statement denotes The therapeutic potential of EPCs in neonatal lung injury has been effectively demonstrated in an oxygen-induced BPD mouse model.
T72 26569-26572 Epistemic_statement denotes 74
T73 26573-26779 Epistemic_statement denotes The therapeutic potential of human amnion epithelial cells (hAECs) has recently been investigated in a sheep model of neonatal lung injury, induced by lipopolysaccharide (LPS) administration in fetal sheep.
T74 27228-27365 Epistemic_statement denotes The low engraftment into the lungs indicates that these hAECs act via immune modulation rather than cell engraftment and differentiation.
T75 27366-27495 Epistemic_statement denotes More detailed assessment of the therapeutic potential of these cells in other models of neonatal lung injury will be of interest.
T76 27496-27671 Epistemic_statement denotes In summary, findings from several exciting studies indicate that a variety of stem/ progenitor cells can prevent and/or regenerate neonatal lung injury in experimental models.
T77 27672-27844 Epistemic_statement denotes Additional studies in different animal models of BPD are necessary to broaden the current knowledge and understanding of the therapeutic potential of stem/progenitor cells.
T78 27845-27982 Epistemic_statement denotes In doing so, further evidence for creating a strong rationale for transitioning this potential breakthrough into clinic can be generated.
T79 27983-28210 Epistemic_statement denotes Although stem/progenitor cell therapies present potential promise in preventing and/or repairing lung injury, many gaps in our knowledge and understanding of stem cell biology in health and disease are yet to be filled (Box 1).
T80 28616-28925 Epistemic_statement denotes 52, 53, [70] [71] [72] [73] [74] [75] However, few of these studies have reported the long-term outcomes (ie, in mid-adult or aged lung) of such stem/ progenitor cell therapies, 52, 71 which is a vital and clinically important area of research that needs to be understood to warrant safe clinical translation.
T81 28926-29274 Epistemic_statement denotes In addition, it would be valuable to understand the effects of such stem/progenitor cell therapies in other animal models of neonatal lung injury closely mimicking the clinical setting (ie, ventilator-induced, fetal/neonatal inflammation-induced), rather than the frequently used hyperoxia-induced model; indeed, this is already being used by some.
T82 29275-29505 Epistemic_statement denotes 75 Current studies highlight the beneficial effects of stem/progenitor cell therapy on attenuating structural and/or molecular alterations to the injured developing lung, yet the effects on lung function are infrequently reported.
T83 29506-29775 Epistemic_statement denotes 52 This aspect of experimental studies requires further investigation and thorough documentation, because Stem Cells and Bronchopulmonary Dysplasia the overall aim of treating neonatal lung injury with stem/progenitor cells is to reduce and/or prevent lung dysfunction.
T84 29776-30077 Epistemic_statement denotes Half a century since the landmark discovery of stem cells by the Canadian researchers Till and McCulloch in 1961, 76 their therapeutic potential in regenerative medicine is now being harnessed for treatment of neonatal lung injury, almost half a century since Northway and colleagues 77 described BPD.
T85 30290-30462 Epistemic_statement denotes However, before safe clinical translation of cell-based therapies is warranted, we must broaden our knowledge and understanding in this novel and exciting area of research.
T86 30628-30712 Epistemic_statement denotes Experimental studies also need to focus on the long-term outcomes of such therapies.
T87 30713-31040 Epistemic_statement denotes By identifying the most appropriate reparative cell(s) and its source, combined with understanding alternative mechanisms of action beyond cell replacement and assessing the short-term and long-term efficacy and safety, we can advance in the quest of providing therapeutic strategies to prevent and repair neonatal lung injury.