Stem Cells Cloning. 2015 Apr 15;8:61-5. doi: 10.2147/SCCAA.S49801. eCollection 2015.
Regenerative medicine in the treatment of idiopathic pulmonary fibrosis: current position.
1Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, University of Pittsburgh Medical Center, Pittsburgh, PA, USA ;Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
2Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
3Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, University of Pittsburgh Medical Center, Pittsburgh, PA, USA ;Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA ; McGowan Institute for Regenerative Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible disease of the lung that has no lasting option for therapy other than transplantation. It is characterized by replacement of the normal lung tissue by fibrotic scarring, honeycombing, and increased levels of myofibroblasts. The underlying causes of IPF are still largely unknown. The focus of the current review is the possible use of stem cell therapy, specifically mesenchymal stem cells (MSCs), a multipotent stromal cell population, which have demonstrated promising data in multiple animal models of pulmonary fibrosis (PF). The most studied source of MSCs is the bone marrow, although they can be found also in the adipose tissueand umbilical cord, as well as in the placenta. MSCs have immunomodulatory and tissue-protective properties that allow them to manipulate the local environment of the injured tissue, ameliorating the inflammation and promoting repair. Because IPF primarily affects older patients, the issue of aging is intrinsically linked to many aspects of the disease, including the age of the stem cells. Animal models have shown the success of MSC therapy in mitigating the fibrotic effects of bleomycin-induced PF. However, bleomycin, the most commonly used model for PF, is imperfect in mimicking IPF as it presents in humans, as the duration of the illness is not parallel or reversible, and honeycombing is not produced. Furthermore, the time of MSC dosage has proven to be critical in determining whether the cells will ultimately have a positive or negative effect on disease progression, since it has been demonstrated that the maximal beneficial effect of MSCs occurs during the early inflammatory phase of the disease and that there is no or negative effect during the late fibrotic phase. Therefore, all the current clinical trials of MSCs and IPF, though promising, should proceed with caution as we move toward true stem cell therapy for this disease.
aging; cell therapy; idiopathic pulmonary fibrosis; lung disease; lung fibrosis; mesenchymal stem cells
Transl Res. 2015 Dec;166(6):554-67. doi: 10.1016/j.trsl.2015.09.004. Epub 2015 Sep 18.
Therapeutic benefits of young, but not old, adipose-derived mesenchymal stem cells in a chronic mouse model of bleomycin-induced pulmonary fibrosis.
1Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, Fla.
2Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, Fla.
3Division of Pediatric Pulmonology, Department of Pediatrics, Leonard M. Miller School of Medicine, University of Miami, Miami, Fla.
4Department of Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, Fla.
5Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY.
6Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, Fla; Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, Fla; Division of Pediatric Pulmonology, Department of Pediatrics, Leonard M. Miller School of Medicine, University of Miami, Miami, Fla..
The observation that pulmonary inflammatory lesions and bleomycin (BLM)-induced pulmonary fibrosis spontaneously resolve in young mice, whereas remaining irreversible in aged mice suggests that impairment of pulmonary regeneration and repair is associated with aging. Because mesenchymal stem cells (MSCs) may promote repair after injury, we postulated that differences in MSCs from aged mice may underlie postinjury fibrosis in aging. The potential for young-donor MSCs to inhibit BLM-induced pulmonary fibrosis in aged male mice (>22 months) has not been studied. Adipose-derived MSCs (ASCs) from young (4 months) and old (22 months) male mice were infused 1 day after intratracheal BLM administration. At 21-day sacrifice, aged BLM mice demonstrated lung fibrosis by Ashcroft score, collagen content, and α(v)-integrin messenger RNA (mRNA) expression. Lung tissue from aged BLM mice receiving young ASCs exhibited decreased fibrosis, matrix metalloproteinase (MMP)-2 activity, oxidative stress, and markers of apoptosis vs BLM controls. Lung mRNA expression of tumor necrosis factor-alpha was also decreased in aged BLM mice receiving young-donor ASCs vs BLM controls. In contrast, old-donor ASC treatment in aged BLM mice did not reduce fibrosis and related markers. On examination of the cells, young-donor ASCs had decreased mRNA expression of MMP-2, insulin-like growth factor (IGF) receptor, and protein kinase B (AKT) activation compared with old-donor ASCs. These results show that the BLM-induced pulmonary fibrosis in aged mice could be blocked by young-donor ASCs and that the mechanisms involve changes in collagen turnover and markers of inflammation.
Keywords: bleomycin, pulmonary fibrosis, idiopathic pulmonary fibrosis, stem cells, aging
Exp Lung Res. 2014 Apr;40(3):117-25. doi: 10.3109/01902148.2014.881930.
The effect of adipose stem cell therapy on pulmonary fibrosis induced by repetitive intratracheal bleomycin in mice.
11Department of Anatomy, Korea University College of Medicine, Inchonro, Seoul , Korea.
Adipose stem cells (ASCs) are detectable in the parenchyma and large airways of lungs after systemic administration, and ameliorate inflammatory infiltration and cell death in animal models of emphysema. We evaluated whether ASC treatment could attenuate lung fibrosis induced by repetitive intratracheal bleomycin administration. Male 8-week-old C57BL/6J mice (control group, bleomycin-only group, and bleomycin-plus-ASC group) were used. Eight biweekly doses of bleomycin were injected intratracheally via an intubation procedure at a dose of 0.04 units in a total volume of 100 μL of sterile saline. During the latter 2 months of the 4-month bleomycin exposure, human ASCs (3 × 10(5)cells) were administered repeatedly via intraperitoneal injection at the same time as bleomycin. Lung tissues were evaluated for histology, collagen content, TUNEL staining, and TGF-β levels. Bronchoalveolar lavage (BAL) was performed for cell counting. Administrations of ASCs ameliorated the deleterious effects of repetitive intratracheal instillation of bleomycin, namely hyperplasia of Club cells (Clara cells) and cuboidal alveolar epithelial cells, infiltration of the perialveolar ducts by inflammatory cells, septal thickening, enlarged alveoli, and extensive fibrosis. Addition of ASC led to suppression of bleomycin-induced epithelial cell apoptosis and expression of TGF-β. These results suggest a useful therapeutic effect of ASCs on pulmonary fibrosis induced by repetitive bleomycin administration. Further studies will be required to evaluate the efficacy of ASC therapy for the treatment of idiopathic pulmonary fibrosis.
KEYWORDS: adipose stem cell, bleomycin, mouse, cell therapy, pulmonary fibrosis