Mesenchymal stem cells for therapeutic applications in pulmonary medicine.

INTRODUCTION: Mesenchymal stem cells (MSCs) of different biological sources are in Phase 1 clinical trials and are being considered for Phase 2 therapy of lung disorders, and lung (progenitor) cells derived from pluripotent stem cells (SCs) are under development in preclinical animal models. SOURCES OF DATA: PubMed.gov and ClinicalTrials.gov. AREAS OF AGREEMENT: There is consensus about the therapeutic potential of transplanted SCs, mainly MSCs, primarily involves paracrine 'bystander' effects that confer protection of the epithelial and endothelial linings of the lung caused by inflammation and/or fibrosis and lead to increased survival in animal models. Clinical trials of Phase 1 indicate safety and suggest that the efficacy of SC therapy in patients with various lung diseases will require a higher dosage than previously evaluated. AREAS OF CONTROVERSY: A growing interest in the re-epithelialization and re-endothelialization of damaged lung tissue involves the putative pulmonary differentiation of exogenous MSCs. Currently, it is not clear whether or not the observed regeneration of distal airways/vasculature is derived from lung-resident and/or transplanted SCs. GROWING POINTS: Important topics under investigation include optimization of the cell source with a decrease in cell population heterogeneity characterized by defined markers, route of delivery for effective treatment, potential dose and therapeutic protocol of SC application, development of quantitative assays and biomarkers of lung disease and repair, and the potential use of tissue engineered lung. AREAS TIMELY FOR DEVELOPING RESEARCH: Ability of MSCs to differentiate into epithelial cells of the lung, use of autologous induced pluripotent SCs (iPSCs) derived from the patients, complete biochemical characterization of the secretome of SCs used for therapy, and the incorporation of simultaneous and/or subsequent treatment with drugs which also aid in lung repair and regeneration. CAUTIONARY NOTE: Although safety of MSC-based cell therapy was proved in Phase 1, efficacy, long-term survival and preservation of lung respiratory function need to be further evaluated, cautioning against hastily translating SCs therapy from animal models of lung injury to clinical trials of patients with lung disorders.