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      Bone Marrow Mononuclear Cells Transplantation in Treatment of Established Bronchopulmonary Dysplasia: A Case Report

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          Abstract

          Patient: Male, newborn

          Final Diagnosis: Bronchopulmonary displasia

          Symptoms: Difficult to breath • patient could not wean from oxygen/premature

          Medication: —

          Clinical Procedure: Bone marrow mononuclear cells transplantation

          Specialty: Pulmonology

          Objective:

          Management of emergency car

          Background:

          Bronchopulmonary dysplasia (BDP) is an incurable disease. This study reports the successful treatment of a 30-week-old neonate with established bronchopulmonary dysplasia by bone marrow mononuclear cells (BM MNCs) transplantation.

          Case Report:

          The preterm infant with BPD requiring continuous oxygen administration for 4 months post-delivery underwent BM MNCs. Bone marrow was obtained from the patient’s iliac crests and mononuclear cells were isolated by density gradient centrifugation method. BM MNCs were delivered via endotracheal and intravenous routes. After BM MNCs transplantation, remarkable improvements were observed in oxygen saturation and lung CT as the infant was gradually weaned off oxygen supply.

          Conclusions:

          BM MNCs transplantation offers promising treatment of BPD.

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          Most cited references10

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          Bone marrow stromal cells attenuate lung injury in a murine model of neonatal chronic lung disease.

          Neonatal chronic lung disease, known as bronchopulmonary dysplasia (BPD), remains a serious complication of prematurity despite advances in the treatment of extremely low birth weight infants. Given the reported protective actions of bone marrow stromal cells (BMSCs; mesenchymal stem cells) in models of lung and cardiovascular injury, we tested their therapeutic potential in a murine model of BPD. Neonatal mice exposed to hyperoxia (75% O(2)) were injected intravenously on Day 4 with either BMSCs or BMSC-conditioned media (CM) and assessed on Day 14 for lung morphometry, vascular changes associated with pulmonary hypertension, and lung cytokine profile. Injection of BMSCs but not pulmonary artery smooth muscle cells (PASMCs) reduced alveolar loss and lung inflammation, and prevented pulmonary hypertension. Although more donor BMSCs engrafted in hyperoxic lungs compared with normoxic controls, the overall low numbers suggest protective mechanisms other than direct tissue repair. Injection of BMSC-CM had a more pronounced effect than BMSCs, preventing both vessel remodeling and alveolar injury. Treated animals had normal alveolar numbers at Day 14 of hyperoxia and a drastically reduced lung neutrophil and macrophage accumulation compared with PASMC-CM-treated controls. Macrophage stimulating factor 1 and osteopontin, both present at high levels in BMSC-CM, may be involved in this immunomodulation. BMSCs act in a paracrine manner via the release of immunomodulatory factors to ameliorate the parenchymal and vascular injury of BPD in vivo. Our study suggests that BMSCs and factor(s) they secrete offer new therapeutic approaches for lung diseases currently lacking effective treatment.
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            Airway delivery of mesenchymal stem cells prevents arrested alveolar growth in neonatal lung injury in rats.

            Bronchopulmonary dysplasia (BPD) and emphysema are characterized by arrested alveolar development or loss of alveoli; both are significant global health problems and currently lack effective therapy. Bone marrow-derived mesenchymal stem cells (BMSCs) prevent adult lung injury, but their therapeutic potential in neonatal lung disease is unknown. We hypothesized that intratracheal delivery of BMSCs would prevent alveolar destruction in experimental BPD. In vitro, BMSC differentiation and migration were assessed using co-culture assays and a modified Boyden chamber. In vivo, the therapeutic potential of BMSCs was assessed in a chronic hyperoxia-induced model of BPD in newborn rats. In vitro, BMSCs developed immunophenotypic and ultrastructural characteristics of type II alveolar epithelial cells (AEC2) (surfactant protein C expression and lamellar bodies) when co-cultured with lung tissue, but not with culture medium alone or liver. Migration assays revealed preferential attraction of BMSCs toward oxygen-damaged lung versus normal lung. In vivo, chronic hyperoxia in newborn rats led to air space enlargement and loss of lung capillaries, and this was associated with a decrease in circulating and resident lung BMSCs. Intratracheal delivery of BMSCs on Postnatal Day 4 improved survival and exercise tolerance while attenuating alveolar and lung vascular injury and pulmonary hypertension. Engrafted BMSCs coexpressed the AEC2-specific marker surfactant protein C. However, engraftment was disproportionately low for cell replacement to account for the therapeutic benefit, suggesting a paracrine-mediated mechanism. In vitro, BMSC-derived conditioned medium prevented O(2)-induced AEC2 apoptosis, accelerated AEC2 wound healing, and enhanced endothelial cord formation. BMSCs prevent arrested alveolar and vascular growth in part through paracrine activity. Stem cell-based therapies may offer new therapeutic avenues for lung diseases that currently lack efficient treatments.
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              Human umbilical cord blood-derived mesenchymal stem cells attenuate hyperoxia-induced lung injury in neonatal rats.

              Recent evidence suggests mesenchymal stem cells (MSCs) can downmodulate bleomycin-induced lung injury, and umbilical cord blood (UCB) is a promising source for human MSCs. This study examined whether intratracheal or intraperitoneal transplantation of human UCB-derived MSCs can attenuate hyperoxia-induced lung injury in immunocompetent newborn rats. Wild-type Sprague-Dawley rats were randomly exposed to 95% oxygen or air from birth. In the transplantation groups, a single dose of PKH26-labeled human UCB-derived MSCs was administered either intratracheally (2 x 10(6) cells) or intraperitoneally (5 x 10(5) cells) at postnatal day (P) 5. At P14, the harvested lungs were examined for morphometric analyses of alveolarization and TUNEL staining, as well as the myeoloperoxidase activity, the level of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and transforming growth factor (TGF)-beta mRNA, alpha-smooth muscle actin (SMA) protein, and collagen levels. Differentiation of MSCs to the respiratory epithelium was also evaluated both in vitro before transplantation and in vivo after transplantation. Despite one fourth dosage of MSCs, significantly more PKH26-labeled donor cells were recovered with intratracheal administration than with intraperitoneal administration both during normoxia and hyperoxia. The hyperoxia-induced increase in the number of TUNEL-positive cells, myeloperoixdase activity, and the level of IL-6 mRNA were significantly attenuated with both intratracheal and intraperitoneal MSCs transplantation. However, the hyperoxia-induced impaired alveolarization and increased the level of TNF-alpha and TGF-beta mRNA, alpha-SMA protein, and collagen were significantly attenuated only with intratracheal MSCs transplantation. MSCs differentiated into respiratory epithelium in vitro and a few PKH26-positive donor cells were colocalized with pro surfactant protein C in the damaged lungs. In conclusion, intratracheal transplantation of human UCB-derived MSCs is more effective than intraperitoneal transplantation in attenuating the hyperoxia-induced lung injury in neonatal rats.
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                Author and article information

                Journal
                Am J Case Rep
                Am J Case Rep
                amjcaserep
                The American Journal of Case Reports
                International Scientific Literature, Inc.
                1941-5923
                2017
                12 October 2017
                : 18
                : 1090-1094
                Affiliations
                [1 ]Department of Stem Cell and Immune Cell, Vinmec Research Institute of Stem Cells and Gene Technology, Hanoi, Vietnam
                [2 ]Department of Neonatology, Vinmec International Hospital, Hanoi, Vietnam
                Author notes

                Authors’ Contribution:

                [A]

                Study Design

                [B]

                Data Collection

                [C]

                Statistical Analysis

                [D]

                Data Interpretation

                [E]

                Manuscript Preparation

                [F]

                Literature Search

                [G]

                Funds Collection

                Corresponding Author: Nguyen Thanh Liem, e-mail: v.liemnt-ceo@ 123456vinmec.com

                Conflict of interest: None declared

                Article
                905244
                10.12659/AJCR.905244
                5652889
                29021519
                f18da12e-c762-4b59-820b-8950f11e8552
                © Am J Case Rep, 2017

                This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International ( CC BY-NC-ND 4.0)

                History
                : 10 May 2017
                : 21 July 2017
                Categories
                Articles

                bone marrow cells,bronchopulmonary dysplasia,stem cell transplantation

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