Intranasal versus Intraperitoneal Delivery of Human Umbilical Cord Tissue–Derived Cultured Mesenchymal Stromal Cells in a Murine Model of Neonatal Lung Injury

Abstract

Clinical trials investigating mesenchymal stromal cell (MSC) therapy for bronchopulmonary dysplasia have been initiated; however, the optimal delivery route and functional effects of MSC therapy in newborns remain incompletely established. We studied the morphologic and functional effects of intranasal versus i.p. MSC administration in a rodent model of neonatal lung injury. Cultured human cord tissue MSCs (0.1, 0.5, or 1 × 10(6) cell per pup) were given intranasally or i.p. to newborn severe combined immunodeficiency-beige mice exposed to 90% O2 from birth; sham controls received an equal volume of phosphate-buffered saline. Lung mechanics, engraftment, lung growth, and alveolarization were evaluated 8 weeks after transplantation. High-dose i.p. MSC administration to newborn mice exposed to 90% O2 resulted in the restoration of normal lung compliance, elastance, and pressure-volume loops (tissue recoil). Histologically, high-dose i.p. MSC administration was associated with alveolar septal widening, suggestive of interstitial matrix modification. Intranasal MSC or lower-dose i.p. administration had no significant effects on lung function or alveolar remodeling. Pulmonary engraftment was rare in all the groups. These findings suggest that high-dose systemic administration of human cultured MSCs can restore normal compliance in neonatally injured lungs, possibly by paracrine modulation of the interstitial matrix. Intranasal delivery had no obvious pulmonary effects.

Therapeutic Effects of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Acute Lung Injury Mice

“…Human umbilical cord-derived mesenchymal stem cells (UC-MSCs) are considered a better choice of MSCs for clinical application because of their easy collection, high cell vitality9, low immunogenicity10, and high paracrine potential for accelerating injury tissue repair processes11. UC-MSCs have potential efficacy in the prevention or treatment of lung injury1213. However, the therapeutic effects and potential molecular mechanism of UC-MSCs in an ALI model remain unclear.…”

Mesenchymal Stromal Cell Therapy in Bronchopulmonary Dysplasia: Systematic Review and Meta-Analysis of Preclinical Studies

“…Liu et al reported a significant dose‐dependent effect of intraperitoneal MSC in restoring total lung capacity, inspiratory capacity, compliance, elastance, and area of PV loop while having no effect on airway resistance. In contrast, intranasal MSC had no obvious effect on lung function.…”

Intussusceptive-like angiogenesis in human fetal lung xenografts: Link with bronchopulmonary dysplasia-associated microvascular dysangiogenesis?

“…The pulmonary microvasculature in these animal models has been relatively neglected or, when studied, has only been reported to be attenuated or diminished in size. Similarly, in our previously described animal models of BPD, which were based on perinatal induction of respiratory epithelial apoptosis 18 or neonatal hyperoxia exposure 19 , the vasculature was linear and non-sprouting within thin septa. To our knowledge, there is at present no valid animal model that replicates the complex and tortuous dysmorphic microvascular alterations observed in infants with severe BPD at postmortem examination 6 .…”