Cell Therapy Trials for Lung Diseases: Progress and Cautions

Weiss, Daniel J.; Ortiz, Luis A.

doi:10.1164/rccm.201302-0351ed

Cited by 38 publications

(27 citation statements)

References 21 publications

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“…There is no available data suggesting that MSC administration once fibrosis is established will decrease fibrosis, rather several studies suggested that MSCs administration at the fibrotic lungs may not be effective, rather may increase lung fibrosis (27, 38, 39). Our attempt to infuse AD-MSC at fibrotic stage on day 14, 17 and 20 post bleomycin did not yield any results since most of the animals did not survive (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…Our attempt to infuse AD-MSC at fibrotic stage on day 14, 17 and 20 post bleomycin did not yield any results since most of the animals did not survive (data not shown). This may be perhaps due to severity of the disease and addressing this question is fundamental because it will not only determine the mechanism of action but also the potential toxicity of MSCs in patients with IPF (39). Similar studies were carried out using pirfenidone by day 15 post bleomycin revealed reduction in hydroxyproline content but did not reduce fibrosis.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Human Adipose-derived Mesenchymal Stem Cells Attenuate Early Stage of Bleomycin Induced Pulmonary Fibrosis: Comparison with Pirfenidone

Reddy

Fonseca

Gowda

et al. 2016

IJSC

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Background and ObjectivesIdiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, invariably fatal fibrotic lung disease with no lasting option for therapy. Mesenchymal stem cells (MSCs) could be a promising modality for the treatment of IPF. Aim of the study was to investigate improvement in survivability and anti-fibrotic efficacy of human adipose-derived mesenchymal stem cells (AD-MSCs) in comparison with pirfenidone in the bleomycin-induced pulmonary fibrosis model.MethodsHuman AD-MSCs were administered intravenously on day 3, 6 and 9 after an intra-tracheal challenge with bleomycin, whereas, pirfenidone was given orally in drinking water at the rate of 100 mg/kg body weight three times a day daily from day 3 onward. AD-MSCs were labelled with PKH-67 before administration to detect engraftment. Disease severity and improvement was assessed and compared between sham control and vehicle control groups using Kaplan-Meier survival analysis, biochemical and molecular analysis, histopathology and high resolution computed tomography (HRCT) parameters at the end of study.ResultsResults demonstrated that AD-MSCs significantly increase survivability; reduce organ weight and collagen deposition better than pirfenidone group. Histological analyses and HRCT of the lung revealed that AD-MSCs afforded protection against bleomycin induced fibrosis and protect architecture of the lung. Gene expression analysis revealed that AD-MSCs potently suppressed pro-fibrotic genes induced by bleomycin. More importantly, AD-MSCs were found to inhibit pro-inflammatory related transcripts.ConclusionsOur results provided direct evidence that AD-MSC-mediated immunomodulation and anti-fibrotic effect in the lungs resulted in marked protection in pulmonary fibrosis, but at an early stage of disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Human Adipose-derived Mesenchymal Stem Cells Attenuate Early Stage of Bleomycin Induced Pulmonary Fibrosis: Comparison with Pirfenidone

Reddy

Fonseca

Gowda

et al. 2016

IJSC

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“…Additional trials are listed to test treatments for pulmonary hypertension (using infusions of endothelial progenitor cells or monocytic bone marrow progenitors) and to assess treatment of pulmonary silicosis using intrabronchial instillations of bone marrow cells 53 . Clinical investigations in Europe have also targeted IPF with cell-based therapy using MSCs 122 .…”

Section: Current Therapuetic Approaches For Lung Regenerationmentioning

confidence: 99%

Lung regeneration: mechanisms, applications and emerging stem cell populations

Kotton

Morrisey

2014

Nat Med

430

367

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Recent studies have shown that the respiratory system has an extensive ability to respond to injury and regenerate lost or damaged cells. The unperturbed adult lung is remarkably quiescent, but after insult or injury progenitor populations can be activated or remaining cells can re-enter the cell cycle. Techniques including cell-lineage tracing and transcriptome analysis have provided novel and exciting insights into how the lungs and trachea regenerate in response to injury and have allowed the identification of pathways important in lung development and regeneration. These studies are now informing approaches for modulating the pathways that may promote endogenous regeneration as well as the generation of exogenous lung cell lineages from pluripotent stem cells. The emerging advances, highlighted in this Review, are providing new techniques and assays for basic mechanistic studies as well as generating new model systems for human disease and strategies for cell replacement.

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“…However, considering that many patients die waiting for a suitable donor, lung diseases are prime candidates for stem cell-based therapies, with more than 100 clinical trials listed at ClinicalTrials.gov 1 . These trials focus largely on the efficacy of mesenchymal cells 2 ; however, on the basis of several preclinical mechanistic studies [3][4][5][6] it is anticipated that any benefit that might arise from such cells would probably occur through paracrine or immunomodulatory effects rather than lung regeneration with engrafted and transdifferentiated donor type cells 7 . Such regeneration represents a major challenge owing to the extremely complex structure of the lung, which comprises more than 40 cell types.…”

mentioning

confidence: 99%

Preconditioning allows engraftment of mouse and human embryonic lung cells, enabling lung repair in mice

Rosen

Shezen

Aronovich

et al. 2015

Nat Med

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Repair of injured lungs represents a longstanding therapeutic challenge. We show that human and mouse embryonic lung tissue from the canalicular stage of development (20-22 weeks of gestation for humans, and embryonic day 15-16 (E15-E16) for mouse) are enriched with progenitors residing in distinct niches. On the basis of the marked analogy to progenitor niches in bone marrow (BM), we attempted strategies similar to BM transplantation, employing sublethal radiation to vacate lung progenitor niches and to reduce stem cell competition. Intravenous infusion of a single cell suspension of canalicular lung tissue from GFP-marked mice or human fetal donors into naphthalene-injured and irradiated syngeneic or SCID mice, respectively, induced marked long-term lung chimerism. Donor type structures or 'patches' contained epithelial, mesenchymal and endothelial cells. Transplantation of differentially labeled E16 mouse lung cells indicated that these patches were probably of clonal origin from the donor. Recipients of the single cell suspension transplant exhibited marked improvement in lung compliance and tissue damping reflecting the energy dissipation in the lung tissues. Our study provides proof of concept for lung reconstitution by canalicular-stage human lung cells after preconditioning of the pulmonary niche.

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Cell Therapy Trials for Lung Diseases: Progress and Cautions

Cited by 38 publications

References 21 publications

Human Adipose-derived Mesenchymal Stem Cells Attenuate Early Stage of Bleomycin Induced Pulmonary Fibrosis: Comparison with Pirfenidone

Human Adipose-derived Mesenchymal Stem Cells Attenuate Early Stage of Bleomycin Induced Pulmonary Fibrosis: Comparison with Pirfenidone

Lung regeneration: mechanisms, applications and emerging stem cell populations

Preconditioning allows engraftment of mouse and human embryonic lung cells, enabling lung repair in mice

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