Publications by authors named "Xianlan Liu"

10 Publications

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Mesenchymal Stromal Cell-Derived Extracellular Vesicles Restore Thymic Architecture and T Cell Function Disrupted by Neonatal Hyperoxia.

Front Immunol 2021 15;12:640595. Epub 2021 Apr 15.

Division of Newborn Medicine & Department of Pediatrics, Boston Children's Hospital, Boston, MA, United States.

Treating premature infants with high oxygen is a routine intervention in the context of neonatal intensive care. Unfortunately, the increase in survival rates is associated with various detrimental sequalae of hyperoxia exposure, most notably bronchopulmonary dysplasia (BPD), a disease of disrupted lung development. The effects of high oxygen exposure on other developing organs of the infant, as well as the possible impact such disrupted development may have on later life remain poorly understood. Using a neonatal mouse model to investigate the effects of hyperoxia on the immature immune system we observed a dramatic involution of the thymic medulla, and this lesion was associated with disrupted FoxP3 regulatory T cell generation and T cell autoreactivity. Significantly, administration of mesenchymal stromal cell-derived extracellular vesicles (MEx) restored thymic medullary architecture and physiological thymocyte profiles. Using single cell transcriptomics, we further demonstrated preferential impact of MEx treatment on the thymic medullary antigen presentation axis, as evidenced by enrichment of antigen presentation and antioxidative-stress related genes in dendritic cells (DCs) and medullary epithelial cells (mTECs). Our study demonstrates that MEx treatment represents a promising restorative therapeutic approach for oxygen-induced thymic injury, thus promoting normal development of both central tolerance and adaptive immunity.
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http://dx.doi.org/10.3389/fimmu.2021.640595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082426PMC
September 2021

Therapeutic Effects of Mesenchymal Stromal Cell-Derived Small Extracellular Vesicles in Oxygen-Induced Multi-Organ Disease: A Developmental Perspective.

Front Cell Dev Biol 2021 16;9:647025. Epub 2021 Mar 16.

Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA, United States.

Despite major advances in neonatal intensive care, infants born at extremely low birth weight still face an increased risk for chronic illness that may persist into adulthood. Pulmonary, retinal, and neurocognitive morbidities associated with preterm birth remain widespread despite interventions designed to minimize organ dysfunction. The design of therapeutic applications for preterm pathologies sharing common underlying triggers, such as fluctuations in oxygen supply or in the inflammatory state, requires alternative strategies that promote anti-inflammatory, pro-angiogenic, and trophic activities-ideally as a unitary treatment. Mesenchymal stem/stromal cell-derived extracellular vesicles (MEx) possess such inherent advantages, and they represent a most promising treatment candidate, as they have been shown to contribute to immunomodulation, homeostasis, and tissue regeneration. Current pre-clinical studies into the MEx mechanism of action are focusing on their restorative capability in the context of preterm birth-related pathologies, albeit not always with a multisystemic focus. This perspective will discuss the pathogenic mechanisms underlying the multisystemic lesions resulting from early-life disruption of normal physiology triggered by high oxygen exposures and pro-inflammatory conditions and introduce the application of MEx as immunomodulators and growth-promoting mediators for multisystem therapy.
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http://dx.doi.org/10.3389/fcell.2021.647025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007882PMC
March 2021

Mesenchymal stromal cell-derived extracellular vesicle therapy prevents preeclamptic physiology through intrauterine immunomodulation†.

Biol Reprod 2021 02;104(2):457-467

Division of Newborn Medicine and Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.

Human umbilical cord-derived mesenchymal stromal cells (MSCs) are a widely recognized treatment modality for a variety of preclinical disease models and have been transitioned to human clinical trials. We have previously shown in neonatal lung disease that the therapeutic capacity of MSCs is conferred by their secreted extracellular vesicles (MEx), which function primarily through immunomodulation. We hypothesize that MEx have significant therapeutic potential pertinent to immune-mediated gestational diseases. Of particular interest is early-onset preeclampsia, which can be caused by alterations of the maternal intrauterine immune environment. Using a heme-oxygenase-1 null mouse model of pregnancy loss with preeclampsia-like features, we examined the preventative effects of maternal MEx treatment early in pregnancy. Heme oxygenase-1 null females (Hmox1-/-) or wild-type control females were bred in homozygous matings followed by evaluation of maternal and fetal parameters. A single dose of MEx was administered intravenously on gestational day (GD)1 to Hmox1-/- females (Hmox1-/- MEx). Compared with untreated Hmox1-/- females, Hmox1-/- MEx-treated pregnancies showed significant improvement in fetal loss, intrauterine growth restriction, placental spiral artery modification, and maternal preeclamptic stigmata. Biodistribution studies demonstrated that MEx localize to a subset of cells in the preimplantation uterus. Further, mass cytometric (CyTOF) evaluation of utero-placental leukocytes in Hmox1-/- MEx versus untreated pregnancies showed alteration in the abundance, surface marker repertoire, and cytokine profiles of multiple immune populations. Our data demonstrate the therapeutic potential of MEx to optimize the intrauterine immune environment and prevent maternal and fetal sequelae of preeclamptic disease.
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http://dx.doi.org/10.1093/biolre/ioaa198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876668PMC
February 2021

Mesenchymal stromal cell-derived small extracellular vesicles restore lung architecture and improve exercise capacity in a model of neonatal hyperoxia-induced lung injury.

J Extracell Vesicles 2020 Jul 13;9(1):1790874. Epub 2020 Jul 13.

Division of Newborn Medicine & Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.

Early administration of mesenchymal stromal cell (MSC)-derived small extracellular vesicles (MEx) has shown considerable promise in experimental models of bronchopulmonary dysplasia (BPD). However, the ability of MEx to reverse the long-term pulmonary complications associated with established BPD remains unknown. In this study, MEx were isolated from media conditioned by human Wharton's Jelly-derived MSC cultures. Newborn mice (FVB strain) were exposed to hyperoxia (HYRX (75% O2)) before returning to room air at postnatal day 14 (PN14). Following prolonged HYRX-exposure, animals received a single MEx dose at PN18 or serial MEx treatments at PN18-39 ("late" intervention). This group was compared to animals that received an early single MEx dose at PN4 ("early" intervention). Animals were harvested at PN28 or 60 for assessment of pulmonary parameters. We found that early and late MEx interventions effectively ameliorated core features of HYRX-induced neonatal lung injury, improving alveolar simplification, pulmonary fibrosis, vascular remodelling and blood vessel loss. Exercise capacity testing and assessment of pulmonary hypertension (PH) showed functional improvements following both early and late MEx interventions. In conclusion, delivery of MEx following prolonged HYRX-exposure improves core features of experimental BPD, restoring lung architecture, decreasing pulmonary fibrosis and vascular muscularization, ameliorating PH and improving exercise capacity. Taken together, delivery of MEx may not only be effective in the immediate neonatal period to prevent the development of BPD but may provide beneficial effects for the management and potentially the reversal of cardiorespiratory complications in infants and children with established BPD.
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http://dx.doi.org/10.1080/20013078.2020.1790874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480622PMC
July 2020

Microcystic pattern and shadowing are independent predictors of ovarian borderline tumors and cystadenofibromas in ultrasound.

Eur Radiol 2021 Jan 11;31(1):45-54. Epub 2020 Aug 11.

Department of Ultrasound, the Second Affiliated Hospital of Fujian Medical University, Licheng District, Quanzhou, 362000, Fujian, China.

Objectives: To determine the sonographic characteristics of borderline tumors (BoTs) and cystadenofibromas (CAFs).

Methods: Preoperative sonograms from consecutive patients who had at least one primary epithelial tumor in the adnexa were retrospectively collected. All tumors were described using the International Ovarian Tumor Analysis terminology. Ultrasound variables were tested using multinomial logistic regression after univariate analysis.

Results: A total of 650 patients were included in this study. Of these, 110 had a CAF, 128 had a BoT, 249 had a cystadenoma (CAD), and 163 had a cystadenocarcinoma (CAC). Nearly half of CAFs and more than half of BoTs and CACs appeared to be unilocular and multilocular solid on the ultrasound images, while CADs were predominantly uni- or multilocular (p < 0.001). Overall, shadowing was identified in 82/650 cases. Sixty-five of 110 (59.1%) CAFs exhibited an acoustic shadow, compared with only 4/249 (1.6%) in CADs, 7/128 (5.5%) in BoTs, and 6/163 (3.7%) in CACs (p < 0.001). Furthermore, 112/650 cases demonstrated microcystic pattern (MCP). Sixty-eight of 128 (53.1%) BoTs exhibited MCP, compared with only 5/249 (2.0%) in CADs, 19/163 (11.7%) in CACs, and 20/110 (18.2%) in CAFs (p < 0.001). Logistic regression analysis revealed that shadowing is an independent predictor of CAFs, while MCP is an independent predictor of BoTs.

Conclusions: Sonographic findings for CAFs and BoTs were complex and partly overlapped with those for CACs. However, proper recognition and utilization of shadowing or MCP may help to correctly discriminate CAFs and BoTs.

Key Points: • Sonographic findings for borderline tumors and cystadenofibromas are complex and mimic malignancy. • Microcystic pattern and shadowing are independent predictors of borderline tumors and cystadenofibromas respectively.
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http://dx.doi.org/10.1007/s00330-020-07113-zDOI Listing
January 2021

Mesenchymal Stromal Cell Exosomes Ameliorate Experimental Bronchopulmonary Dysplasia and Restore Lung Function through Macrophage Immunomodulation.

Am J Respir Crit Care Med 2018 01;197(1):104-116

1 Division of Newborn Medicine, Department of Medicine, and.

Rationale: Mesenchymal stem/stromal cell (MSC) therapies have shown promise in preclinical models of pathologies relevant to newborn medicine, such as bronchopulmonary dysplasia (BPD). We have reported that the therapeutic capacity of MSCs is comprised in their secretome, and demonstrated that the therapeutic vectors are exosomes produced by MSCs (MSC-exos).

Objectives: To assess efficacy of MSC-exo treatment in a preclinical model of BPD and to investigate mechanisms underlying MSC-exo therapeutic action.

Methods: Exosomes were isolated from media conditioned by human MSC cultures. Newborn mice were exposed to hyperoxia (HYRX; 75% O), treated with exosomes on Postnatal Day (PN) 4 and returned to room air on PN7. Treated animals and appropriate controls were harvested on PN7, -14, or -42 for assessment of pulmonary parameters.

Measurements And Main Results: HYRX-exposed mice presented with pronounced alveolar simplification, fibrosis, and pulmonary vascular remodeling, which was effectively ameliorated by MSC-exo treatment. Pulmonary function tests and assessment of pulmonary hypertension showed functional improvements after MSC-exo treatment. Lung mRNA sequencing demonstrated that MSC-exo treatment induced pleiotropic effects on gene expression associated with HYRX-induced inflammation and immune responses. MSC-exos modulate the macrophage phenotype fulcrum, suppressing the proinflammatory "M1" state and augmenting an antiinflammatory "M2-like" state, both in vitro and in vivo.

Conclusions: MSC-exo treatment blunts HYRX-associated inflammation and alters the hyperoxic lung transcriptome. This results in alleviation of HYRX-induced BPD, improvement of lung function, decrease in fibrosis and pulmonary vascular remodeling, and amelioration of pulmonary hypertension. The MSC-exo mechanism of action is associated with modulation of lung macrophage phenotype.
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http://dx.doi.org/10.1164/rccm.201705-0925OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765387PMC
January 2018

Vasculoprotective effects of heme oxygenase-1 in a murine model of hyperoxia-induced bronchopulmonary dysplasia.

Am J Physiol Lung Cell Mol Physiol 2012 Apr 27;302(8):L775-84. Epub 2012 Jan 27.

Harvard Division of Newborn Medicine, Children’s Hospital Boston, MA 02115, USA.

Bronchopulmonary dysplasia (BPD) is characterized by simplified alveolarization and arrested vascular development of the lung with associated evidence of endothelial dysfunction, inflammation, increased oxidative damage, and iron deposition. Heme oxygenase-1 (HO-1) has been reported to be protective in the pathogenesis of diseases of inflammatory and oxidative etiology. Because HO-1 is involved in the response to oxidative stress produced by hyperoxia and is critical for cellular heme and iron homeostasis, it could play a protective role in BPD. Therefore, we investigated the effect of HO-1 in hyperoxia-induced lung injury using a neonatal transgenic mouse model with constitutive lung-specific HO-1 overexpression. Hyperoxia triggered an increase in pulmonary inflammation, arterial remodeling, and right ventricular hypertrophy that was attenuated by HO-1 overexpression. In addition, hyperoxia led to pulmonary edema, hemosiderosis, and a decrease in blood vessel number, all of which were markedly improved in HO-1 overexpressing mice. The protective vascular response may be mediated at least in part by carbon monoxide, due to its anti-inflammatory, antiproliferative, and antiapoptotic properties. HO-1 overexpression, however, did not prevent alveolar simplification nor altered the levels of ferritin and lactoferrin, proteins involved in iron binding and transport. Thus the protective mechanisms elicited by HO-1 overexpression primarily preserve vascular growth and barrier function through iron-independent, antioxidant, and anti-inflammatory pathways.
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http://dx.doi.org/10.1152/ajplung.00196.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3331581PMC
April 2012

Early macrophage recruitment and alternative activation are critical for the later development of hypoxia-induced pulmonary hypertension.

Circulation 2011 May 25;123(18):1986-95. Epub 2011 Apr 25.

Division of Newborn Medicine, Children's Hospital Boston, Harvard Medical School, MA 02115, USA.

Background: Lung inflammation precedes the development of hypoxia-induced pulmonary hypertension (HPH); however, its role in the pathogenesis of HPH is poorly understood. We sought to characterize the hypoxic inflammatory response and to elucidate its role in the development of HPH. We also aimed to investigate the mechanisms by which heme oxygenase-1, an anti-inflammatory enzyme, is protective in HPH.

Methods And Results: We generated bitransgenic mice that overexpress human heme oxygenase-1 under doxycycline control in an inducible, lung-specific manner. Hypoxic exposure of mice in the absence of doxycycline resulted in early transient accumulation of monocytes/macrophages in the bronchoalveolar lavage. Alveolar macrophages acquired an alternatively activated phenotype (M2) in response to hypoxia, characterized by the expression of found in inflammatory zone-1, arginase-1, and chitinase-3-like-3. A brief 2-day pulse of doxycycline delayed, but did not prevent, the peak of hypoxic inflammation, and could not protect against HPH. In contrast, a 7-day doxycycline treatment sustained high heme oxygenase-1 levels during the entire period of hypoxic inflammation, inhibited macrophage accumulation and activation, induced macrophage interleukin-10 expression, and prevented the development of HPH. Supernatants from hypoxic M2 macrophages promoted the proliferation of pulmonary artery smooth muscle cells, whereas treatment with carbon monoxide, a heme oxygenase-1 enzymatic product, abrogated this effect.

Conclusions: Early recruitment and alternative activation of macrophages in hypoxic lungs are critical for the later development of HPH. Heme oxygenase-1 may confer protection from HPH by effectively modifying the macrophage activation state in hypoxia.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.110.978627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3125055PMC
May 2011

Mesenchymal stromal cells expressing heme oxygenase-1 reverse pulmonary hypertension.

Stem Cells 2011 Jan;29(1):99-107

Division of Newborn Medicine, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115, USA.

Pulmonary arterial hypertension (PAH) remains a serious disease, and although current treatments may prolong and improve quality of life, search for novel and effective therapies is warranted. Using genetically modified mouse lines, we tested the ability of bone marrow-derived stromal cells (mesenchymal stem cells [MSCs]) to treat chronic hypoxia-induced PAH. Recipient mice were exposed for 5 weeks to normobaric hypoxia (8%-10% O(2)), MSC preparations were delivered through jugular vein injection and their effect on PAH was assessed after two additional weeks in hypoxia. Donor MSCs derived from wild-type (WT) mice or heme oxygenase-1 (HO-1) null mice (Hmox1(KO)) conferred partial protection from PAH when transplanted into WT or Hmox1(KO) recipients, whereas treatment with MSCs isolated from transgenic mice harboring a human HO-1 transgene under the control of surfactant protein C promoter (SH01 line) reversed established disease in WT recipients. SH01-MSC treatment of Hmox1(KO) animals, which develop right ventricular (RV) infarction under prolonged hypoxia, resulted in normal RV systolic pressure, significant reduction of RV hypertrophy and prevention of RV infarction. Donor MSCs isolated from a bitransgenic mouse line with doxycycline-inducible, lung-specific expression of HO-1 exhibited similar therapeutic efficacy only on doxycycline treatment of the recipients. In vitro experiments indicate that potential mechanisms of MSC action include modulation of hypoxia-induced lung inflammation and inhibition of smooth muscle cell proliferation. Cumulatively, our results demonstrate that MSCs ameliorate chronic hypoxia-induced PAH and their efficacy is highly augmented by lung-specific HO-1 expression in the transplanted cells, suggesting an interplay between HO-1-dependent and HO-1-independent protective pathways.
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http://dx.doi.org/10.1002/stem.548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422740PMC
January 2011
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