Stem cell therapies for chronic obstructive pulmonary disease: current status of pre-clinical studies and clinical trials

Abstract

Chronic obstructive pulmonary disease (COPD) is a respiratory disease that has a major impact worldwide. The currently-available drugs mainly focus on relieving the symptoms of COPD patients. Novel regenerative therapeutic approaches have been investigated with the aim of repairing or replacing the injured functional structures of the respiratory system. We summarized the progress made by regenerative therapies for COPD by analyzing results from both pre-clinical studies and completed clinical trials. These approaches include the application of exogenous stem cells or small molecules to stimulate the regeneration by endogenous lung stem/progenitor cells. Exogenous mesenchymal stem cells (MSCs) have been reported to repair the structure and improve the function of the injured respiratory system in COPD models. However, the studies that used MSCs in patients with moderate-to-severe COPD patients did not lead to clear respiratory functional improvements. Exogenous human lung stem cells applied to cryo-injured (CI) lungs of mice have been shown to organize into human-like pulmonary structures, indicating a new property of stem cells that is potentially capable of curing COPD patients. Small molecules like retinoic acid has been shown to lead to regeneration and repair of the damaged lung structures in COPD mouse models probably by activation of endogenous lung stem/progenitor cells. However, retinoic acid or agonists of retinoic acid receptor administered to moderate or severe COPD patients did not improve the density and function of the damaged lung. These novel regenerative approaches have failed in preliminary clinical trials, possibly due to the advanced severity of the disease. Further work should be done to develop the current regenerative approaches for curing patients at different stages of COPD. We suggest that some modifications of the approach in the clinical studies may lead to more successful outcomes of regenerative therapy for COPD.

Potential Using of Fat-derived Stromal Cells in the Treatment of Active Disease, and also, in Both Pre- and Post-Periods in COVID-19

“…The regenerative approaches have included extrinsic cell therapy such as the infusion of exogenous stem cells to repair the damaged structure of the respiratory system and intrinsic cell therapy such as the administration of small molecules to stimulate the endogenous lung stem/ progenitor cells for regeneration and replacement of the damaged structures [17]. Adipose derived stromal cells , using their immunomodulatory properties and their differentiation ability, can prevent lung tissue death by counteracting the cytokine storm and regeneration and reconstruction of damaged tissues .…”

“…Additionally, AD-MSCs seem to have greater anti-inflammatory potential than BM-MSCs, since they secrete higher levels of bioactive mediators, and have been shown to attenuate lung inflammation in different models of lung injury [ 16 ]. In experimental pulmonary system models, the causes of unsuccessful MSC treatment have been reported as insufficient cell number, condition of cells, cell types, frequency and timing of administration and insufficient doses of administration [ 15 , 17 ]. These problems can be solved with stromal cells from adipose tissue.…”

New normal: two aspects of adipose tissue in COVID-19—treat and threat?

“…Additionally, ADSCs seem to have greater antiinflammatory potential than BM-MSCs, since they secrete higher levels of bioactive mediators, and have been shown to attenuate lung inflammation in different models of lung injury [25]. In experimental pulmonary system models, the causes of unsuccessful MSC treatment have been reported as insufficient cell number, condition of cells, cell types, frequency and timing of administration, and insufficient doses of administration [24,26] These problems can be solved with stromal cells from adipose tissue. Because a large number of cells can be obtained in high quality and not only as MSC, but also as a cocktail with other stromal cells.…”

“…The regenerative approaches have included extrinsic cell therapy such as the infusion of exogenous stem cells to repair the damaged structure of the respiratory system and intrinsic cell therapy such as the administration of small molecules to stimulate the endogenous lung stem/progenitor cells for regeneration and replacement of the damaged structures [26] Adipose-derived stromal cells, using their immunomodulatory properties and their differentiation ability, can prevent lung tissue death by counteracting the cytokine storm and regeneration and reconstruction of damaged tissues. Notably, it has been proved that MSC-released cytokines can potently inhibit neutrophil intravasation and enhance the differentiation of macrophages.…”

COPD Pathogenesis

“…[39][40][41] Similarly, attempts to regenerate normal mechanical forces by restoration of elastic fibers or alveolar septa have not resulted in a clinically promising agent, although further development of stem cell therapies could make this approach more effective. 42 Our laboratory tested the use of nebulized HA as a prospective form of treatment for pulmonary emphysema. A 2-week, randomized, double-blind, placebo-controlled, Phase IIa safety trial was performed in patients with smoke-related COPD to evaluate the safety and efficacy of nebulized HA.…”