Intranasal delivery of human umbilical cord Wharton's jelly mesenchymal stromal cells restores lung alveolarization and vascularization in experimental bronchopulmonary dysplasia

Abstract

Bronchopulmonary dysplasia (BPD) is a devastating lung condition that develops in premature newborns exposed to prolonged mechanical ventilation and supplemental oxygen. Significant morbidity and mortality are associated with this costly disease and effective therapies are limited. Mesenchymal stem/stromal cells (MSCs) are multipotent cells that can repair injured tissue by secreting paracrine factors known to restore the function and integrity of injured lung epithelium and endothelium. Most preclinical studies showing therapeutic efficacy of MSCs for BPD are administered either intratracheally or intravenously. The purpose of this study was to examine the feasibility and effectiveness of human cord tissue-derived MSC administration given via the intranasal route.Human umbilical cord tissue MSCs were isolated, characterized, and given intranasally (500 000 cells per 20 μL) to a hyperoxia-induced rat model of BPD. Lung alveolarization, vascularization, and pulmonary vascular remodeling were restored in animals receiving MSC treatment. Gene and protein analysis suggest the beneficial effects of MSCs were attributed, in part, to a concerted effort targeting angiogenesis, immunomodulation, wound healing, and cell survival. These findings are clinically significant, as neonates who develop BPD have altered alveolar development, decreased pulmonary vascularization and chronic inflammation, all resulting in impaired tissue healing. Our study is the first to report the intranasal delivery of umbilical cord Wharton's jelly MSCs in experimental BPD is feasible, noninvasive, and an effective route that may bear clinical applicability. K E Y W O R D Sbronchopulmonary dysplasia, intranasal delivery, mesenchymal stromal cell, neonate, umbilical cord

Present and Future of Bronchopulmonary Dysplasia

“…Kourembanas' group [185] was the first to demonstrate the beneficial effects of intravenous MSCs or MSC-conditioned medium (CM) in an animal model of hyperoxia-induced BPD. Their promising results were confirmed by other investigators using intravenous, intratracheal [186][187][188][189][190][191][192][193][194] and, more recently, intraperitoneal [195] and intranasal [196] modes of administration. These treatments lowered the levels of inflammatory mediators like IL−6 and TNF-α [197], and the expression of angiotensin II, angiotensin II type 1 receptor, and angiotensin-converting enzyme [198], which are involved in the development of BPD.…”

Exosome therapeutics for lung regenerative medicine

“…18,26] Nonimmunogenic [54] Can be selected to carry specific proteins, receptors, or nucleic acids for gene therapy via cell culture microenvironment [9,16,35,64, B. 26] Stable during cryopreservation [16] Naturally crosses cell membranes and the BBB [63] Regulate tissue homoeostasis [36,54] Initiates tissue repair and regeneration [2,17,34,36,40,48] Released by most cell types, enabling tissue-specific signalling [48,54] Long-lasting paracrine effects [39,40]…”

“… 18 , 26 ] Nonimmunogenic [ 54 ] Can be selected to carry specific proteins, receptors, or nucleic acids for gene therapy via cell culture microenvironment [ 9 , 16 , 35 , 64 , B. 26 ] Stable during cryopreservation [ 16 ] Naturally crosses cell membranes and the BBB [ 63 ] Regulate tissue homoeostasis [ 36 , 54 ] Initiates tissue repair and regeneration [ 2 , 17 , 34 , 36 , 40 , 48 ] Released by most cell types, enabling tissue-specific signalling [ 48 , 54 ] Long-lasting paracrine effects [ 39 , 40 ] Cons Difficult to produce enough yield to be effective in humans [ 6 ] All isolation techniques have cons, including time, monetary cost, forming aggregates, introducing contaminants [ 6 , 54 ] Systemic administration has not reflected targeting potential [ 6 ] Difficult to produce enough yield to be effective in humans [ 10 , 64 ] All isolation techniques have cons, including time, monetary cost, forming aggregates, introducing contaminants [ 16 , 63 , 66 ] No single way to manufacture exosomes of a specific potency [ 10 , 16 ] Representative Companies Anjarium Biosciences ArunA Biomedical Codiak Biosciences Evox Therapeutics Exogenus Therapeutics Aegle Therapeutics BreStem Therapeutics Capricor Therapeutics Kimera Exosomes ReNeuron Tavec Pharma Xollent Biotech …”

Fighting the War Against COVID-19 via Cell-Based Regenerative Medicine: Lessons Learned from 1918 Spanish Flu and Other Previous Pandemics

“…Intranasal administration of MSCs has been tested with neurological diseases, such as stroke, highlighting the homing capability of MSCs [ 132 ]. MSCs delivered through the nose have also been shown to be able to restore alveolar growth and vascular development in rat models of bronchopulmonary dysplasia [ 133 ]. These relevant findings from other disease indications highlight the many modes of delivery for stem cell therapy for COVID-19, which must be taken into consideration in future clinical trials.…”