Human mesenchymal stem cell therapy: Potential advances for reducing cystic fibrosis infection and organ inflammation

Innovation in cystic fibrosis (CF) supportive care, including implementing new antimicrobial agents, improved physiotherapy, and highly effective modulators therapy, has advanced patient survival into the 4th and 5th decades of life. However, even with these remarkable improvements in therapy, CF patients continue to suffer from pulmonary infection and other visceral organ complications associated with long-term deficient cystic fibrosis transmembrane conductance regulator (CFTR) expression. Human mesenchymal stem cells (MSCs) have been utilized in tissue engineering based upon their capacity to provide structural components of mesenchymal tissues. An alternative role of MSCs, however is their versatile utilization as cell-based infusion powerhouses due to the unique capacity to deliver milieu specific soluble biologic factors, promoting immune supportive antimicrobial and anti-inflammatory potency. MSCs derived from umbilical cord blood, bone marrow, adipose and other tissues can be expanded in ex vivo using good manufacturing procedure facilities for a safe, unique therapeutic to reduce and limit CF infection and facilitate the resolution of multi-organ inflammation. In our efforts, we conducted extensive preclinical development and validation of an allogeneic derived bone marrow derived MSC product in preparation for a clinical trial in CF. In this process, potency models were developed to ensure the functional capacity of the MSC product to provide clinical benefit. In vitro, murine in vivo and patient tissue ex vivo potency models were utilized to follow MSC anti-infective and anti-inflammatory potency associated with the CFTR deficient environment. We showed in our "First in CF" clinical trial that the allogeneic MSCs obtained from healthy volunteer bone marrow samples were safe. The advent of improved CF care measures and exciting new small molecules has changed the survival and morbidity phenotype of patients with CF, however, there are CF patients who cannot tolerate or have genotypes that are non-responsive to modulators. Additionally, even with the small molecule therapy, CF patients are living longer, but without genetic correction, with the CF disease manifestation aggravated by the continuance of pre-existing CFTR-associated clinical issues such as ongoing inflammation. MSCs secrete bio-active factors that enhance and protect tissue function and can promote "self-immune" regulation. These properties can provide therapeutic support for the traditional and changing face of CF disease clinical complications. Further, MSC-derived bio-active factors can directly mitigate colonizing pathogens' survival by producing antimicrobial peptides (AMPs) which change the pathogen surface and increase host recognition, elimination, and sensitivity to antibiotics. Herein, we review the potential of MSC therapeutics for treating many facets of CF, emphasizing the potential for providing great additive therapeutics for managing morbidity and quality of life.