Mesenchymal cells, a hound for COPD

2023-12-15 10:27:57

Mesenchymal cells, a hound for COPD

“These mesenchymal cells respond to lung inflammation like a hound chasing a hare, obtaining an anti-inflammatory effect and, above all, achieving greater vascular proliferation,” highlights the Dr. Rosa María Malo de Molina Ruizpulmonologist at the Puerta de Hierro University Hospital in Majadahonda.

“These mesenchymal cells even restore the protease/antiprotease balance and have a certain antibacterial effect,” adds the specialist and associate professor at the Faculty of Medicine of the Autonomous University of Madrid.

“In any case, all the positive results of the referenced clinical studies are still insufficient and have shown limited efficacy, despite the fact that this experimental treatment already reaches the required safety levels,” he emphasizes.

“In addition, the different investigations underway would need to standardize protocols, optimize candidates and improve the preconditioning of the cells in order to increase their migratory and regenerative capacity,” he indicates.

How do mesenchymal stem cells act against lung tissue damaged by COPD?

Stem cells are those that have clonogenic capacity; that is, they proliferate until they form genetically identical cells. Its primary function is to maintain, generate and replace the differentiated cells of each tissue, whether due to tissue self-renewal or damage to organic tissue.

These mesenchymal stem cells form colonies with a fibroblastic appearance and are found in the bone marrow and in many other tissues, such as adipose and dental pulp, as well as in the umbilical cord and amniotic fluid, two especially interesting sources for research related to the epoch

“If we think that mesenchymal cells can be great candidates for the treatment of chronic obstructive pulmonary disease, it is because their lung regenerative capacity has been proven in mouse models (laboratory mice),” says Dr. Malo de Molina.

Briefly, the procedure is performed by biopsy taking bone marrow from a male mouse. These extracted mesenchymal cells are then cultured.

“They undergo preconditioning of precise stimuli, such as exposure to inflammatory environments, pretreatment with drugs or other chemicals, even genetic engineering to make them more effective during the treatment of the target disease,” he explains.

Once regenerated in the laboratory, these cells are infused into another mouse, in this case female.

“During the research process, the appearance of the Y chromosome (one of the two chromosomes -X and Y- of the cells of the male animal) will be observed in the lung tissue of the female recipient animal (which should only show two X chromosomes), as shown dot red in the photograph,” he clarifies.

“But the most fascinating aspect of current research is its paracrine effect (action exerted by a substance secreted by a cell on local cellular environments): these mesenchymal cells are capable of generating an immunomodulatory effect,” he highlights.

“They decrease the action of the immune system, in this case for the better. “They begin to release many anti-inflammatory markers, proteins, that help control pro-inflammatory T lymphocytes (CD4 and CD 8), while increasing the activity of regulatory T lymphocytes (anti-inflammatory),” he adds.

“And these therapeutic cells have a very interesting characteristic in relation to COPD: they ensure that macrophages – a type of white blood cell – are activated and switch to a more anti-inflammatory phenotype, M2; which helps reduce certain markers, such as the pro-inflammatory interleukin IL6,” he details.

“However, the most striking characteristic of these mesenchymal cells in COPD is that they increase markers of vascular proliferation. “They regenerate and cause more blood flow in the damaged lung organ (neovascularization),” he believes.

“In addition, mesenchymal cells improve the protease-antiprotease balance, reduce cell death and apoptosis, and have a certain antibacterial effect because they increase the antimicrobial peptide,” explains Dr. Malo de Molina Ruiz.

It should be remembered that the epoc It is a disease defined by a chronic limitation of airflow, with a progressive and poorly reversible course, which is associated with an inflammatory response in the lung lobes caused by smoke of the tabacco.

What happens in clinical trials with COPD patients?

According to ClinicalTrials.gov, a registry and database of clinical trials prepared by the United States National Library of Medicine from the National Institutes of Health (NIH), there were up to eight in October 2023. clinical trials on mesenchymal cell therapy and COPD.

Insights from five of the published clinical trials: in all of them stem cells work to alleviate the symptoms associated with chronic airway disease.

In this trial, mesenchymal cells from bone marrow were infused into nine patients in two doses, one week apart; These cells were labeled with indium chloride (111In): 30 minutes after each dose, uptake was increased, mainly in the lungs, although it then decreased over a week. Seven days later the beneficial effects began to diminish.

In the research it was observed that in the areas of the lung where there is greater lung destruction (red arrows), this uptake (visualized through indium) is practically non-existent. It is located more in areas that are structurally preserved. There is a correlation between the degree of uptake and severity, such that it captures less in patients whose lung function is very impaired.

In this clinical trial, with a sample size of 62 patients (74% completed the two-year study period), an early and significant decrease in C-reactive protein (CRP) levels was observed in patients treated with mesenchymal cells. . In patients with CRP above 4, an improvement in lung function is observed.

This other study proves that mesenchymal stromal cells (MSCs) can reduce inflammation and promote tissue repair in severe pulmonary emphysema.

The trial is carried out on seven patients with heterogeneous emphysema who were candidates for lung volume reduction surgery: they were operated on twice, each time on one lung, to compare the tissues of both areas, with and without mesenchymal cell therapy from their bone marrow. .

Increased expression of CD31 protein is observed after surgery and MSC treatment, suggesting the responsiveness of microvascular endothelial cells in severely affected parts of the lung (angiogenesis).

This study analyzed the action of bone marrow mesenchymal cells in patients with advanced heterogeneous emphysema, candidates for endoscopic lung volume reduction VE (installation of one-way endobronchial valves that block air entry into the target lobe, but allow air exit). of said lobe).

They divide the patients into two groups: one has the endobronchial valves placed without infusing the cells, while the other has them infused directly into the affected bronchus before installing the EVs. The observation was carried out for 90 days.

Not only were there no complications or adverse effects, something already observed with intravenous therapy in different studies, but there was a decrease in circulating C-reactive protein at 30 and 90 days, reducing the inflammatory process and mitigating the complications of VE in patients with severe COPD.

Furthermore, an improvement is achieved in the combined BODE index in these patients (airflow obstruction, dyspnea, exercise capacity and quality of life).

In this last study, with twenty patients (9 in stage C and 11 in stage D, according to GOLD classification) and without a control group, the safety and efficacy of mesenchymal stem cells derived from the umbilical cord were evaluated.

After six months of study, an improvement in quality of life measured by the CAT index (impact of COPD on patients’ quality of life) was observed in relation to dyspnea and the number of exacerbations.

This videoblog has been prepared based on the intervention of Dr. Rosa Malo de Molina at the debate table “COPD is getting younger and increasingly has a woman’s name” from the scientific program “Visionaries, Innovation and Future in Respiratory Diseases”; a professional meeting that took place on October 6, 2023 in the assembly hall of the La Princesa University Hospital in Madrid.