Mitochondrial transfer from bone-marrow–derived stromal cells to pulmonary alveoli protects against acute lung injury

Abstract

Bone marrow-derived stromal cells (BMSCs) protect against acute lung injury (ALI). To determine the role of BMSC mitochondria in the protection, we airway-instilled mice first with lipopolysaccharide (LPS), then with mouse BMSCs (mBMSCs). Live optical studies revealed that mBMSCs formed connexin 43 (Cx43)-containing gap junctional channels (GJCs) with the alveolar epithelium, releasing mitochondria-containing microvesicles that the epithelium engulfed. The presence of BMSC mitochondria in the epithelium was evident optically, as also by the presence of human mitochondrial DNA in mouse lungs in which we instilled human BMSCs (hBMSCs). The mitochondrial transfer increased alveolar ATP. LPS-induced ALI, indicated by alveolar leukocytosis and protein leak, inhibition of surfactant secretion and high mortality, was markedly abrogated by wild type mBMSCs, but not by mutant, GJC-incompetent mBMSCs, or by mBMSCs with dysfunctional mitochondria. This is the first evidence that BMSCs protect against ALI by restituting alveolar bioenergetics through Cx43-dependent alveolar attachment and mitochondrial transfer.

Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer

“…Mesenchymal stromal cells (MSCs) are increasingly recognized as a promising candidate therapy for ARDS (6). We and others have reported that MSCs improve survival, reduce inflammation, and enhance bacterial clearance in preclinical models of lung injury (7)(8)(9)(10)(11)(12)(13)(14). Secretion of paracrine factors, modulation of host cells via secretion of extracellular vesicles (EVs), and mitochondrial transfer were shown to be important for the therapeutic effects of MSCs in these studies.…”

Mesenchymal stem cells: mechanisms of potential therapeutic benefit in ARDS and sepsis

“…65 Finally, MSCs seem able to aff ect tissue repair through the delivery of extracellular vesicles 68,69 and direct mitochondrial transfer. 70 Although a detailed exploration of this scientifi c literature is beyond the scope of this review, table 5 shows a brief overview of several representative studies.…”

“…Islam et al 70 In a murine lung injury model using intratracheal LPS, MSCs attached to alveoli and formed nanotubes through which mitochondria-containing microvesicles were transferred to the alveolar epithelium; this transfer ameliorated lung injury…”

Adult stem cells: potential implications for perioperative medicine

“…These xenogeneic MSCs formed gap junction channels with host murine cells and transferred mitochondria through the formation of microvesicles. 18 This was observed by microscopy of these transfers as well as by the presence of persistent human mitochondrial DNA in the recipient mouse lungs. Functionally, mitochondrial transfer resulted in increased adenosine triphosphate (ATP) formation and improved survival of these animals.…”

“…Ces CSM exogènes ont formé des canaux de jonction communicante avec les cellules murines hôtes et transféré des mitochondries en formant des microvésicules. 18 Ces transferts ont été observés par microscope, et on a également noté la présence d'ADN mitochondrial humain persistant dans les poumons murins récipiendaires. D'un point de vue fonctionnel, le transfert mitochondrial a entraîné une augmentation de la formation d'adénosine triphosphate (ATP) et une amélioration de la survie de ces animaux.…”