Boosting therapeutic efficacy of mesenchymal stem cells in pulmonary fibrosis: The role of genetic modification and preconditioning strategies

Our plain-English summary of Boosting therapeutic efficacy of mesenchymal stem cells in pulmonary fibrosis: The role of genetic modification and preconditioning strategies, by M. Mehrabani, S. Mohammadyar, M.A. Rajizadeh, et al (Iranian Journal of Basic Medical Sciences, 2023).

The study

• Authors: M. Mehrabani, S. Mohammadyar, M.A. Rajizadeh, M.A. Bejeshk, B. Ahmadi, M.H. Nematollahi, M. Mirtajaddini Goki, K. Bahrampour Juybari, A. Amirkhosravi
• Journal: Iranian Journal of Basic Medical Sciences
• Published: 2023;26(9):1001-1015
• Type of article: Review
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Pulmonary fibrosis (PF) is the end stage of severe lung diseases, in which the lung parenchyma is replaced by fibrous scar tissue. The result is a remarkable reduction in pulmonary compliance, which may lead to respiratory failure and even death. Idiopathic pulmonary fibrosis (IPF) is the most prevalent form of PF, with no reasonable etiology. However, some factors are believed to be behind the etiology of PF, including prolonged administration of several medications (e.g., bleomycin and amiodarone), environmental contaminant exposure (e.g., gases, asbestos, and silica), and certain systemic diseases (e.g., systemic lupus erythematosus). Despite significant developments in the diagnostic approach to PF in the last few years, efforts to find more effective treatments remain challenging. With their immunomodulatory, anti-inflammatory, and anti-fibrotic properties, stem cells may provide a promising approach for treating a broad spectrum of fibrotic conditions. However, they may lose their biological functions after long-term in vitro culture or exposure to harsh in vivo situations. To overcome these limitations, numerous modification techniques, such as genetic modification, preconditioning, and optimization of cultivation methods for stem cell therapy, have been adopted. Herein, we summarize the previous investigations that have been designed to assess the effects of stem cell preconditioning or genetic modification on the regenerative capacity of stem cells in PF.

In plain English

This article was a review, not an original study. The authors summarized earlier research on making mesenchymal stem cells, a type of adult stem cell, more effective as a treatment for pulmonary fibrosis (lung scarring). The abstract listed asbestos, along with gases and silica, among environmental exposures believed to contribute to pulmonary fibrosis. The review did not describe studies specifically testing treatment for asbestos-related pulmonary fibrosis. The authors described clinical trials of stem cell treatment. Most were phase 1 safety trials in idiopathic pulmonary fibrosis; one small trial treated four silicosis patients. They then summarized animal studies, mostly in mice and rats with fibrosis caused by bleomycin, silica or radiation. Many of these studies genetically modified or preconditioned the stem cells (for example with low oxygen) before use; others targeted stem cells already in the lungs or used particles released by preconditioned cells. Some reviewed studies found no advantage from preconditioning. The authors concluded that these techniques promoted the cells' therapeutic potential. They noted safety concerns with modified cells, said animal models do not fully reflect human disease, and called for more research.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review of previously published studies (narrative review)
• Who was studied: Published studies, mainly preclinical animal studies of pulmonary fibrosis plus several early-phase clinical trials of stem cell therapy, mostly in patients with idiopathic pulmonary fibrosis (IPF). The review did not state how many studies it covered or how they were selected.
• Exposure: The review was about stem cell treatments, not about any exposure. Asbestos was mentioned only in the abstract, as one of the environmental contaminants believed to be behind pulmonary fibrosis. The animal studies reviewed used bleomycin, silica, radiation, hyperoxia and other agents to cause lung injury or fibrosis.
• Main results:
  • Among the clinical trials the review described, most were phase 1 safety trials in mild to moderate IPF. The authors knew of only one phase 2 study.
  • The review described a non-randomized, uncontrolled trial (Liu et al.) of four patients with silicosis-related lung fibrosis. These patients received their own bone marrow stem cells modified to carry the human HGF gene. The review's table reported that average FVC (a lung function measure) was not significantly different before and after treatment, while SpO2 (blood oxygen saturation) was significantly enhanced.
  • The authors stated that many preclinical studies supported genetically modified stem cells in animal models of pulmonary fibrosis. One example was a 2017 rat study of silica-induced fibrosis using stem cells over-expressing BMP-7.
  • Not every reviewed animal approach modified cells before giving them. In one mouse study (Ji et al.), siRNA was delivered in micelles to lung-resident stem cells already in the lungs. In another (systemic sclerosis mice), extracellular vesicles from preconditioned stem cells were given instead of the cells themselves.
  • The review also described studies where preconditioning did not help. In one mouse study, the investigators concluded there was no preference for preconditioned over non-preconditioned cells. In another, pretreatment with NMDA weakened the stem cells' anti-fibrotic effects.
  • The authors noted that, in preclinical studies, modified stem cells did not remove scar-tissue deposits, restore injured lung lining, or eliminate fibroblasts.
• The authors' conclusion: The authors concluded that preconditioning and genetic modification promoted the therapeutic potential of transplanted stem cells. They said more focused research is needed to overcome the disadvantages and determine the best strategies.
• Limitations the authors state:
  • Genetically engineered stem cells may raise safety concerns and lead to unpredictable outcomes.
  • Preclinical studies tested the cells only in lung fibrosis models, whereas many real patients are old or have other illnesses.
  • Animal models do not fully reflect human disease processes.
  • There are no well-defined, optimal protocols for preconditioning.

Topics

Medical terms in this study, explained in our Lexicon: STEM, Pulmonary Fibrosis, Parenchyma, Idiopathic, Etiology.

Related studies

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• Mesenchymal stem cells modulate lung injury — A.R. Brody, K.D. Salazar, et al. (2010)
• Genetic factors predicting IFN-gamma generation potential in patients with sarcoidosis and after haematopoietic stem cell transplantation — A. Lange (2008)
• Epithelial-mesenchymal transition involved in pulmonary fibrosis induced by multi-walled carbon nanotubes via TGF-beta/Smad signaling pathway — T. Chen, H. Nie, et al. (2014)
• In vitro and in vivo therapeutic efficacy of the PPAR-γ agonist troglitazone in combination with cisplatin against malignant pleural mesothelioma cell growth — N. Hamaguchi, H. Hamada, et al. (2010)
• The therapeutic efficacy of S-1 against orthotopically implanted human pleural mesothelioma cells in severe combined immunodeficient mice — T.T. Van, M. Hanibuchi, et al. (2011)

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