The clinical use of regenerative therapy in COPD.

This is a summary of the article published by Systems Medicine, University of Rome, Tor Vergata, Rome; in the International Journal of COPD 2014:9 1389–1396.

Many devastating and currently untreatable human diseases arise from the loss or malfunction of specific cell types in the body. This is particularly true for age-related diseases such as lung diseases, neurologic degenerative diseases, type 2 diabetes, and heart failure, as well as for other medical conditions such as trauma, infarction, and burns. Frequently, patients affected by these kind of diseases are limited to organ or tissue transplantation as their only treatment option, but there are only a few organ and tissue donors, and as a consequence the discrepancy between organ need and organ availability is huge.

Furthermore, post transplantation life is conditioned by a lifelong need for immunosuppressive therapy, a high rate of morbidity, a poor quality of life, and a variable prognosis. Regenerative therapy or stem cell therapy is an emerging field of treatment based on stimulation of endogenous resident stem cells or administration of exogenous stem cells to treat diseases or injury and to replace malfunctioning or damaged tissues.

Classically, stem cells are functionally defined as cells showing indefinite self-renewal as well as a clonal, multipotent differentiation repertoire within a cellular hierarchy.5 Regenerative therapy is a promising and rapidly growing area of investigation involving ex vivo bioengineering of functional tissues that could be implanted into patients, and thus it can be considered an alternative to organ transplantation.

 

Global burden of COPD and limitations to current management strategies

Chronic obstructive pulmonary disease (COPD) represents a common cause of morbidity and mortality worldwide, with an increasing and substantial economic and social burden.

According to World Health Organization estimates, around 65 million people have moderate to severe COPD; more than 3 million people die of COPD each year, which corresponds to 5% of all deaths globally; and almost 90% of COPD deaths occur in low- and middle-income countries.

It is the fifth leading cause of death. Total deaths from COPD are projected to increase by more than 30% in the next 10 years unless urgent action is taken to reduce the underlying risk factors, especially tobacco use. Estimates suggest COPD will become the third leading cause of death worldwide in 2030. The enormous burden of COPD requires effective treatment that is able to influence the natural history of the disease.

Chronic inflammation plays a central role in COPD. It is characterized by increased numbers of neutrophils, activated macrophages, and activated T lymphocytes. All this will result in the destruction of alveolar tissue (formation of emphysema), inhibition of normal repair and defense mechanisms (fibrosis formation in distal airways), and airflow obstruction expressed primarily by increased numbers of goblet cells, mucus gland hyperplasia, fibrosis, narrowing and reduction in the number of small airways, and airway collapse because of the destruction of the attachments of the alveolar wall resulting in emphysema.

The management of COPD actually includes primary and secondary prevention, early detection, staging of severity, assessment of reversibility with bronchodilators and inhaled corticosteroids, chronic pharmacotherapy, pulmonary rehabilitation, and treatment of comorbidities.

When respiratory failure is detected, long-term oxygen therapy must be prescribed, and in some cases (characterized by emphysema), lung surgery, including lung volume reduction, should be considered. The introduction and the association of new bronchodilators into the therapeutic choices of COPD have significantly improved the quality of life of patients.

However, current therapeutic approaches for COPD do not allow us to reduce the decline of lung function and to interfere with the progressive and unfavorable course of the disease.

Moreover, anti-inflammatory therapies currently available provide little or no benefit in patients with COPD and may have detrimental effects.

Therefore, all available therapeutic options are actually considered symptomatic, and there is no effective treatment for the formation of emphysema caused by the destruction of alveolar tissue, which is one of the biggest challenges in the development of therapeutic agents for COPD.

Clinical use of regenerative therapy in lung diseases.

Stem cells are considered to be capable of self-renewal and differentiation into several cellular subtypes, depending on their origin and the resident microenvironment. In humans, stem cells can be subdivided into two main categories: embryonic stem cells and adult stem cells.

The latter are located in tissues such as blood, Bone Marrow (BM), adipose tissue, kidney, liver, heart, and the lungs and can be subdivided into multipotent (eg, mesenchymal stem cells [MSCs]) or unipotent (eg, epithelial and endothelial progenitor cells) types on the basis of their differentiation capacity, whereas embryonic stem cells that originate from embryonic blastocystis provide a source of cells throughout the life and act during wound healing.

Current evidence suggests that in the lung, these cells may participate in tissue homeostasis and regeneration after injury and are located within the lung itself in distal airway niches, called resident progenitor cells (alveolar, endothelial, and interstitial), or in distant sites such as the blood, Bone Marrow, adipose tissue, and other sites. The lung could respond to injury and stress by activating stem cell populations and/or by re-entering the cell cycle to repopulate lost cells.

Endothelial progenitor cells were initially evaluated in the treatment of pulmonary hypertension. Later, because of the great need to find effective therapies to treat patients affected by end-stage chronic lung diseases, there has been a growing number of studies on stem cells and cell therapies in lung biology and diseases.

Because it is not difficult to instill exogenous cells into the lung through both the airway and circulation, it is expected that the efficacy of cell delivery is naturally high. Actually, this is very interesting because it seems to offer a real therapeutic approach to a disease that, lung transplantation apart, has no proven therapies to modify its course.

In genetically predisposed individuals or in patients with chronic lung disease, these cells lose in part or completely their regenerative and differentiative capacity and cause abnormal healing tissue repair and restoration. In addition, a limited reservoir of resident stem cells causes the same effect. Therefore, it seems likely that alveologenesis might also be induced by the reactivation of developmental pathways that are in an inactive state.

Potentials of mesenchymal stem cells and low-level laser.

Cell therapy with stem cells represents a potential novel therapeutic approach to degenerative diseases. There are reports in the literature showing pulmonary regeneration after the use of Bone Marrow (BM) cells. In fact, BM cells infused in the blood stream can be recovered or detected in pulmonary tissue.

MSCs are considered a potential therapy in COPD because of their immunomodulatory effects and the ability to regenerate type 1 and 2 cells in the airspace.

MSCs derive from mesoderm and show a multilineage potential, as they have the capacity to give rise to blood, skeletal muscle cells, vascular, fat, and urogenital systems, as well as to connective tissues throughout the body.

Because of their unlimited self-renewal capacity, MSCs show that an in vitro high expansion potential, a genetic and phenotypic stability, can be easily isolated from a small aspirate of BM expanded with high efficiency, shipped from the laboratory to the bedside.

MSCs show anti-inflammatory, immunomodulatory, and regenerative capacities. They secrete anti- inflammatory cytokines that modify the microenvironment within the damaged tissues. They also exert immunomodulatory effects by direct cell-to-cell contact. In fact, MSCs inhibit autoimmune T-cell responses and increase the number of regulatory T cells.

MSCs also inhibit the development and differentiation of dendritic cells and can selectively channel autoimmune T cells to apoptosis. Moreover, MSCs are able to migrate to sites of tissue injury and have strong immunosuppressive properties that can be exploited for successful autologous as well as heterologous transplantations. In 2009, an innovative Phase I clinical study on the use of autologous bone marrow mononuclear cells (BMMCs) in patients with pulmonary emphysema demonstrated that the administration of autologous cells with a pool of BMMCs in patients with advanced-stage COPD is a safe procedure without significant adverse effects. Furthermore, the reports from patients showed that in the period after the infusion of BMMCs until 20 months later, there was pulmonary function improvement and slowing down of the progressive degenerative condition in terms of maintenance or even increase in the forced expiratory volume in 1 second and forced vital capacity, and increase in forced expiratory volume in 1 second/forced vital capacity. BMMCs had an improvement in their clinical condition, a greater time tolerance without O2 intake, a greater capacity on exertion evaluated as walking distance, without significant fall in O2 saturation, and meaningful improvement in the quality of life, as well as a clinical stable condition.

A follow-up of up to 3 years showed an improvement in laboratory para meters (spirometry) and a slowing down in the process of pathological degeneration. In addition, patients reported improvements in the clinical condition and quality of life. These results suggest a change in the natural process of the disease.

A new and interesting field of investigation is “regenerative photobiostimulation,” or having the ability to enhance lung regenerative properties by means of low-level laser irradiation. Low-level laser therapy contemplates the application of electromagnetic radiations, and its beneficial properties include anti-inflammatory activity, growth factor production, stimulation of angiogenesis, and direct stem cell effects. These effects are mediated through a process that is still not clearly defined and does not involve thermal energy. In most cases, irrespective of the treated condition or the modality of administration, therapy with stem cells appears relatively safe.

Conclusion

At this time, COPD treatment is based on the administration of drugs that are able to reduce symptoms and prevent exacerbations. However, these therapies do not allow for changing the natural history of the disease. Animal and human studies have demonstrated that tissue-specific stem cells and BM-derived cells contribute to lung tissue regeneration and protection, and thus administration of exogenous stem/progenitor cells or the humoral factors responsible for the activation of endogenous stem/progenitor cells may be a potent next-generation therapy for COPD.  The use of BM-derived stem cells could allow us to repair and regenerate the damaged tissue present in COPD by means of their engraftment into the lung.

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