Bone marrow progenitors in inflammation and repair: new vistas in respiratory biology and pathophysiology (original) (raw)
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Bone marrow-derived cells as progenitors of lung alveolar epithelium
Development, 2001
We assessed the capacity of plastic-adherent cultured bone marrow cells to serve as precursors of differentiated parenchymal cells of the lung. By intravenously delivering lacZ-labeled cells into wild-type recipient mice after bleomycin-induced lung injury, we detected marrow-derived cells engrafted in recipient lung parenchyma as cells with the morphological and molecular phenotype of type I pneumocytes of the alveolar epithelium. At no time after marrow cell injection, did we detect any engraftment as type II pneumocytes. In addition, we found that cultured and fresh aspirates of bone marrow cells can express the type I pneumocyte markers, T1α and aquaporin-5. These observations challenge the current belief that adult alveolar type I epithelial cells invariably arise from local precursor cells and raise the possibility of using injected marrow-derived cells for therapy of lung diseases characterized by extensive alveolar damage.
Bone Marrow Stem Cell Contribution to Pulmonary Homeostasis and Disease
Journal of Bone Marrow Research, 2015
The understanding of bone marrow stem cell plasticity and contribution of bone marrow stem cells to pathophysiology is evolving with the advent of innovative technologies. Recent data has led to new mechanistic insights in the field of mesenchymal stem cell (MSC) research, and an increased appreciation for the plasticity of the hematopoietic stem cell (HSC). In this review, we discuss current research examining the origin of pulmonary cell types from endogenous lung stem and progenitor cells as well as bone marrow-derived stem cells (MSCs and HSCs) and their contributions to lung homeostasis and pathology. We specifically highlight recent findings from our laboratory that demonstrate an HSC origin for pulmonary fibroblasts based on transplantation of a clonal population of cells derived from a single HSC. These findings demonstrate the importance of developing an understanding of the sources of effector cells in disease state. Finally, a perspective is given on the potential clinical implications of these studies and others addressing stem cell contributions to lung tissue homeostasis and pathology.
Bone Marrow Stromal Cells Attenuate Lung Injury in a Murine Model of Neonatal Chronic Lung Disease
American Journal of Respiratory and Critical Care Medicine, 2009
Rationale: 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. Objectives: 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. Methods: Neonatal mice exposed to hyperoxia (75% O 2 ) were injected intravenously on Day 4 with either BMSCs or BMSCconditioned media (CM) and assessed on Day 14 for lung morphometry, vascular changes associated with pulmonary hypertension, and lung cytokine profile. Measurements and Main Results: 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. Conclusions: 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.
Retention of human bone marrow-derived cells in murine lungs following bleomycin-induced lung injury
AJP: Lung Cellular and Molecular Physiology, 2008
We studied the capacity of adult human bone marrow-derived cells (BMDC) to incorporate into distal lung of immunodeficient mice following lung injury. Immunodeficient NOD/SCID and NOD/SCID/ 2 microglobulin ( 2M) null mice were administered bleomycin (bleo) or saline intranasally. 1, 2, 3 and 4 days after bleo or saline, human BMDC labeled with CellTrackerâ„¢ Green CMFDA (5-chloromethylfluorescein diacetate) were infused intravenously. Retention of CMFDA + cells was maximal when delivered 4 days after bleo treatment. 7 days after bleo, <0.005% of enzymatically dispersed lung cells from NOD/SCID mice were CMFDA + , which increased 10-100 fold in NOD/SCID/ 2M null mice. Pre-incubation of BMDC with Diprotin A, a reversible inhibitor of CD26 peptidase activity that enhances the Stromal-derived factor-1 (SDF-1/CXCL12)/CXCR4 axis, resulted in a 30% increase in the percentage of CMFDA + cells retained in the lung. These data indicate that human BMDC can be identified in lungs of mice following injury, albeit at low levels, and this may be modestly enhanced by manipulation of the SDF-1/CXCR4 axis. Given the overall low number of human cells detected, methods to increase homing and retention of adult BMDC, and consideration of other stem cell populations, will likely be required to facilitate engraftment in the treatment of lung injury.
American Journal of Physiology-lung Cellular and Molecular Physiology, 2007
Bone marrow-derived mesenchymal stem cells (BMDMSCs) appear to be important in repair of the chronic lung injury caused by bleomycin in mice. To determine effects of these BMDMSCs on an acute inflammatory response, we injected C57BL/6 mice intraperitoneally with 1mg/kg endotoxin followed either by intravenous infusion of 5 x10 5 BMDMSCs, the same number of lung fibroblasts or an equal volume of normal saline solution. Lungs harvested 6, 24 and 48 hours and 14 days after endotoxin showed that BMDMSC administration prevented endotoxin induced lung inflammation, injury and edema. Although we were able to detect donor cells in the lungs at 1 day after endotoxin, by 14 days no donor cells were detected. BMDMSC administration suppressed the endotoxin induced increase in circulating pro-inflammatory cytokines without decreasing circulating levels of anti-inflammatory mediators. Ex vivo cocultures of BMDMSC and lung cells from endotoxemic animals demonstrated a bilateral conversation in which lung cells stimulated proliferation and migration of stem cells and suppressed pro-inflammatory cytokine production by lung cells. We conclude that BMDMSCs decrease both the systemic and local inflammatory responses induced by endotoxin. These effects do not require either lung engraftment or differentiation of the stem cells and are due at least in part to the production of stem cell chemoattractants by the lungs and to humoral and physical interactions between stem cells and lung cells. We speculate that mobilization of this population of BMDMSCs may be a general mechanism for modulating an acute inflammatory response.
Nonhematopoietic Cells are the Primary Source of Bone Marrow-Derived Lung Epithelial Cells
STEM CELLS, 2012
Previous studies have demonstrated that bone marrow (BM)-derived cells differentiate into nonhematopoietic cells of multiple tissues. To date, it remains unknown which population(s) of BM cells are primarily responsible for this engraftment. To test the hypothesis that nonhematopoietic stem cells in the BM are the primary source of marrow-derived lung epithelial cells, either wild-type hematopoietic or nonhematopoietic BM cells were transplanted into irradiated surfactant-protein-C (SPC)-null mice. Donor-derived, SPC-positive type 2 pneumocytes were predominantly detected in the lungs of mice receiving purified nonhematopoietic cells and were absent from mice receiving purified hematopoietic stem and progenitor cells. We conclude that cells contained in the nonhematopoietic fraction of the BM are the primary source of marrow-derived lung epithelial cells. These nonhematopoietic cells may represent a primitive stem cell population residing in adult BM. STEM CELLS 2012;30:491-499
Hypoimmunogenic and immunomodulatory nature of human bone marrow mesenchymal stem cells
he capacity of bone marrow mesenchymal stem cells (BMSCs) to extend their multi lineage differentiation potential beyond the confines of their own lineage has interested researchers for over a decade and half. Their hypoimmunogenic nature and immunomodulatory properties have added a new dimension to regenerative medicine, making them even more attractive as a potential source for cell based therapies to treat several degenerative and immune mediated diseases.
MSC from fetal and adult lungs possess lung-specific properties compared to bone marrow-derived MSC
Scientific Reports, 2016
Mesenchymal stromal cells (MSC) are multipotent cells with regenerative and immune-modulatory properties. Therefore, MSC have been proposed as a potential cell-therapy for bronchiolitis obliterans syndrome (BOS). On the other hand, there are publications demonstrating that MSC might be involved in the development of BOS. Despite limited knowledge regarding the functional role of tissue-resident lung-MSC, several clinical trials have been performed using MSC, particularly bone marrow (BM)derived MSC, for various lung diseases. We aimed to compare lung-MSC with the well-characterized BM-MSC. Furthermore, MSC isolated from lung-transplanted patients with BOS were compared to patients without BOS. Our study show that lung-MSCs are smaller, possess a higher colony-forming capacity and have a different cytokine profile compared to BM-MSC. Utilizing gene expression profiling, 89 genes including lung-specific FOXF1 and HOXB5 were found to be significantly different between BM-MSC and lung-MSC. No significant differences in cytokine secretion or gene expression were found between MSC isolated from BOS patients compared recipients without BOS. These data demonstrate that lung-resident MSC possess lung-specific properties. Furthermore, these results show that MSC isolated from lung-transplanted patients with BOS do not have an altered phenotype compared to MSC isolated from good outcome recipients. Mesenchymal stromal cells (MSC) have potent immune-regulatory and regenerative functions and they are therefore promising candidates for cell therapy approaches to treat a variety of different diseases including severe diseases of the lung, such as idiopathic pulmonary fibrosis (IPF) 1 , chronic obstructive pulmonary disease (COPD) 2 and acute respiratory distress syndrome (ARDS) 3. The only curative treatment of severe lung diseases like IPF and COPD at present is lung-transplantation. However, chronic rejection, which is manifested as bronchiolitis obliterans syndrome (BOS)/obliterative bronchiolitis, is a severe complication affecting the survival after a lung-transplantation. The hallmark of this complication is the fibrotic obliteration of the peripheral airways 4 , which is a fibro-proliferative disease for which inflammation has been shown to be an important driving factor. It has therefore been suggested that MSC might be a treatment option. Although MSC have been used in clinical trials for the treatment of severe lung diseases, not much is known about the primary resident lung-MSC. Open questions are for example if the lung-MSC are altered in diseases such as BOS and how lung-resident MSC differ from the bone marrow (BM)-derived MSC, the predominant MSC source in clinical trials? Therefore, the current study aimed to investigate the tissue specificity of MSC isolated from lung tissues (fetal and adult) and to compare them to the extensively studied BM-derived MSC. Furthermore, we aimed to investigate whether MSC isolated from lung-transplanted patients with BOS were different from MSC isolated from good outcome recipients. Our results demonstrate that although lung-derived