Mesenchymal stem cell bioenergetics and apoptosis are associated with risk for bronchopulmonary dysplasia in extremely low birth weight infants

Abstract

Oxidant stress contributes significantly to the pathogenesis of bronchopulmonary dysplasia (BPD) in extremely low birth weight (ELBW) infants. Mitochondrial function regulates oxidant stress responses as well as pluripotency and regenerative ability of mesenchymal stem cells (MSCs) which are critical mediators of lung development. This study was conducted to test whether differences in endogenous MSC mitochondrial bioenergetics, proliferation and survival are associated with BPD risk in ELBW infants. Umbilical cord-derived MSCs of ELBW infants who later died or developed moderate/severe BPD had lower oxygen consumption and aconitase activity but higher extracellular acidification—indicative of mitochondrial dysfunction and increased oxidant stress—when compared to MSCs from infants who survived with no/mild BPD. Hyperoxia-exposed MSCs from infants who died or developed moderate/severe BPD also had lower PINK1 expression but higher TOM20 expression and numbers of mitochondria/cell, indicating that these cells had decreased mitophagy. Finally, these MSCs were also noted to proliferate at lower rates but undergo more apoptosis in cell cultures when compared to MSCs from infants who survived with no/mild BPD. These results indicate that mitochondrial bioenergetic dysfunction and mitophagy deficit induced by oxidant stress may lead to depletion of the endogenous MSC pool and subsequent disruption of lung development in ELBW infants at increased risk for BPD.

Platelet Activating Factor Activity Modulates Hyperoxic Neonatal Lung Injury Severity

“…Another interesting observation of our study was the upregulation of the NAD+ signaling pathway in hyperoxia-exposed PTAFR KO mice compared to WT mice, particularly the increased expression of the mitochondrial enzyme Hmgcs2. Our group has previously shown that mitochondrial bioenergetic and metabolic function of human umbilical venous endothelial cells and mesenchymal stem cells are predictors of risk for BPD in infants (48, 49). Hmgcs2 is a key regulator of ketogenesis which has been found to act as an endogenous protective program that reduces activation of inflammatory macrophages during inflammatory processes that can lead to ARDS (50).…”

Mesenchymal stromal/stem cells and bronchopulmonary dysplasia

“…In a study exploring the correlation between mitochondrial function and the MSC function, electron transport chain complex-IV activity, basal and maximal oxygen consumption rates, spare respiratory capacity, and ATP-linked oxygen consumption rate were reduced. Proton leak was increased in MSCs from extremely low birth weight infants who either perished or developed moderate/severe BPD, compared to MSCs from infants who survived with none to mild BPD ( Hazra et al, 2022 ).…”

“…As a result, oxidative stress-induced mitochondrial dysfunction could lead to MSC depletion, thus obstructing lung development. Another finding described that MSCs from infants who died or developed moderate/severe BPD after O2 treatment showed lower PINK1 expression, implying decreased mitophagy ( Hazra et al, 2022 ). The antioxidant stanniocalcin-1 was also reduced in fetal lung MSCs exposed to hyperoxia ( Mobius et al, 2019 ).…”

Bronchopulmonary dysplasia in adults: Exploring pathogenesis and phenotype

“…31 Furthermore, dysregulation of upstream TGF-β and NF-κB pathways leads to disruption, apoptosis, and depletion of the pulmonary mesenchymal stem cells, which is closely linked to development of BPD. 31,51 The net results are remodeling of the extracellular matrix, persistent inflammation, and dysregulated growth factor signaling that impede normal lung development. 31,52 2.2 | Pro-inflammatory pathways associated with BPD…”

“…Postnatally, high levels of IL‐1β, IL‐6, IL‐8, and TNF‐ α contribute to the development of pulmonary edema, alveolar macrophage activation, neutrophil chemotaxis, increased activation of proteases, and inactivation of surfactant 31 . Furthermore, dysregulation of upstream TGF‐β and NF‐κB pathways leads to disruption, apoptosis, and depletion of the pulmonary mesenchymal stem cells, which is closely linked to development of BPD 31,51 . The net results are remodeling of the extracellular matrix, persistent inflammation, and dysregulated growth factor signaling that impede normal lung development 31,52 …”