Mesenchymal Stem/Stromal Cells Therapy for Sepsis and Acute Respiratory Distress Syndrome

Abstract

Sepsis and acute respiratory distress syndrome (ARDS) constitute devastating conditions with high morbidity and mortality. Sepsis results from abnormal host immune response, with evidence for both pro- and anti-inflammatory activation present from the earliest phases. The “proinflammatory” response predominates initially causing host injury, with later-phase sepsis characterized by immune cell hypofunction and opportunistic superinfection. ARDS is characterized by inflammation and disruption of the alveolar-capillary membrane leading to injury and lung dysfunction. Sepsis is the most common cause of ARDS. Approximately 20% of deaths worldwide in 2017 were due to sepsis, while ARDS occurs in over 10% of all intensive care unit patients and results in a mortality of 30 to 45%. Given the fact that sepsis and ARDS share some—but not all—underlying pathophysiologic injury mechanisms, the lack of specific therapies, and their frequent coexistence in the critically ill, it makes sense to consider therapies for both conditions together. In this article, we will focus on the therapeutic potential of mesenchymal stem/stromal cells (MSCs). MSCs are available from several tissues, including bone marrow, umbilical cord, and adipose tissue. Allogeneic administration is feasible, an important advantage for acute conditions like sepsis or ARDS. They possess diverse mechanisms of action of relevance to sepsis and ARDS, including direct and indirect antibacterial actions, potent effects on the innate and adaptive response, and pro-reparative effects. MSCs can be preactivated thereby potentiating their effects, while the use of their extracellular vesicles can avoid whole cell administration. While early-phase clinical trials suggest safety, considerable challenges exist in moving forward to phase III efficacy studies, and to implementation as a therapy should they prove effective.

CD39+ Regulatory T Cells Attenuate Lipopolysaccharide-Induced Acute Lung Injury via Autophagy and the ERK/FOS Pathway

“…Cell-based therapy gradually gained the attention of researchers due to its effective control of disease initiation and progression by cell replacement, including autologous hematopoietic stem cells, mesenchymal, and related stem cells. While early-phase clinical trials suggest that the allogeneic administration of mesenchymal stem/stromal cells is safe, considerable challenges exist in moving forward to phase III efficacy studies ( 11 ). Tregs, as an immune regulatory cell, is extremely suitable for allogeneic administration; however, the mechanism underlying the use of Tregs for clinical treatment requires further exploration.…”

“…Several novel pharmacological therapeutics, including β-2 agonists ( 5 ), statins ( 6 , 7 ), aspirin ( 8 ), nitric oxide ( 9 ), and keratinocyte growth factor ( 10 ) also showed no obvious clinical benefit. To date, while cell-based approaches, primarily using mesenchymal stem/stromal cells represents the most promising therapy, research remains stagnated in early-phase clinical trials ( 11 ). Therefore, there is an urgency to identify innovative and effective therapeutics that can be used to target ARDS.…”

Regulation of Inflammatory Cytokine Storms by Mesenchymal Stem Cells

“…Systemic administration of mesenchymal stem cells pretreated with interleukin-1β (β-mesenchymal stem cells) is more effective than untreated mesenchymal stem cells in improving the symptoms of sepsis in mice and increasing the survival rate. In addition, β-mesenchymal stem cells can effectively induce macrophages to differentiate into the anti-inflammatory M2 phenotype through paracrine activity ( 72 ). The purpose of staphylococcal enterotoxin B (SEB) pretreatment is to prolong the survival time of transplanted mesenchymal stem cells and induce the production of cytoprotective agents, antiapoptotic agents and anti-inflammatory factors by these cells.…”

“…The results of the first phase of the Chinese Ischemic Stroke Subclassification (CISS) trial provide additional short-term data, showing that the administration of up to 250 million freshly cultured allogeneic bone marrow mesenchymal stem cells is safe for patients with septic shock. These data should give intensive care researchers additional reasons to continue the second phase of the trial to evaluate the efficacy and safety of bone marrow mesenchymal stem cells in the treatment of septic shock ( 80 ) ( Table 1 ).…”

Table_1.docx

“…Several novel pharmacological therapeutics, including b-2 agonists (5), statins (6,7), aspirin (8), nitric oxide (9), and keratinocyte growth factor (10) also showed no obvious clinical benefit. To date, while cell-based approaches, primarily using mesenchymal stem/stromal cells represents the most promising therapy, research remains stagnated in early-phase clinical trials (11). Therefore, there is an urgency to identify innovative and effective therapeutics that can be used to target ARDS.…”