Translation:Li Yanping Editor:Wei Yaping
②MSCs and Myocardial Injury in Sepsis. Septic Induced Myocardial Dysfunction (SIMD) is one of the most common complications of sepsis. The pathogenic factors of SIMD include the release of myocardial suppressive factors, upregulation of NO, impaired myocardial calcium homeostasis, and mitochondrial dysfunction. SIMD primarily manifests as myocardial ischemia and hypoxia, impaired myocardial contractility, and reduced left ventricular ejection fraction (EF), leading to inadequate tissue and organ perfusion. Toll-like receptors (TLRs) on the myocardial cell membrane activate downstream mTOR/NF-κB and mTOR/Akt signaling pathways by recognizing pathogen-associated molecular patterns and danger-associated molecular patterns, resulting in the release of inflammatory factors such as TNF-α and IL-6, which directly cause myocardial injury. These inflammatory factors activate myocardial endothelial cells, leading to increased secretion of inducible nitric oxide synthase (iNOS) and excessive NO production. Excessive NO inhibits L-type calcium channels and myocardial mitochondrial function, leading to contractile dysfunction and decreased cardiac output. Furthermore, the ratio of anti-apoptotic proteins to pro-apoptotic proteins decreases in sepsis, resulting in myocardial injury.
Multiple studies have reported that MSCs weaken inflammatory cell infiltration in cardiomyocytes during sepsis, alleviate myocardial injury, and improve myocardial contractility. Wu et al. reported that MSCs can significantly improve cardiac EF by reducing the expression of TLRs; inhibiting NF-κB signaling pathways; and decreasing levels of inflammatory factors such as IL-1β, IL-6, and TNF-α in the plasma and myocardium of septic mice. Weil et al. demonstrated that, in addition to lowering myocardial inflammatory factor levels, MSCs can also reduce the frequency of myocardial contractions, thereby improving myocardial function. Additionally, MSCs have been shown to secrete exosomes rich in miRNA-223, which inhibit myocardial inflammatory responses and alleviate myocardial injury. In summary, MSCs can weaken inflammatory responses by inhibiting inflammatory signaling pathways and secreting exosomes, suppress NO release, improve myocardial calcium channel activity and mitochondrial function, and alleviate myocardial injury in sepsis.
③Mesenchymal Stem Cells and Septic Liver Injury. The liver exhibits the most intense inflammatory response in sepsis. Peripheral blood lipopolysaccharides stimulate Kupffer cells to secrete high mobility group box 1 (HMGB1); in the presence of HMGB1, immune cells release inflammatory factors such as TNF-α and IL-6. Studies have confirmed that TNF-α plays a crucial role in septic liver injury. Hepatocytes are rich in TNF-α receptors, and TNF-α can directly cause liver injury. Furthermore, TNF-α stimulates the release of other inflammatory factors such as IL-6 and IL-1β; HMGB1 interacts with these factors, forming an inflammatory cascade that exacerbates liver injury. Additionally, TNF-α induces hepatocyte apoptosis and recruits and activates inflammatory cells, such as neutrophils, further worsening liver injury. Oxidative stress can increase levels of ROS and NO in the liver, disrupting epithelial integrity, increasing liver permeability, and triggering cholestasis.
The amplification of the inflammatory response is the primary cause of sepsis-induced liver injury. MSCs can inhibit the inflammatory response and the migration of inflammatory cells to the liver, thereby alleviating liver injury. Several studies have shown that MSCs can inhibit the release of TNF-α, IL-6, and monocyte chemotactic protein (MCP)-1, upregulate anti-inflammatory factors IL-10 and IL-4 to correct immune imbalance. Additionally, MSCs can inhibit the migration and activation of neutrophils in the liver, thereby alleviating inflammation-induced liver injury. Research has shown that adipose tissue-derived MSCs secrete TNF receptor 1, which weakens apoptosis and inflammatory responses in the liver, improving survival in septic mice. Furthermore, MSCs can promote macrophage polarization towards the M2 phenotype, clear pathogens, increase liver glycogen reserves, reduce hepatic oxidative stress, and lower plasma levels of aspartate aminotransferase and alanine aminotransferase.
④Mesenchymal Stem Cells and Septic Kidney Injury. Sepsis-associated kidney injury (SAKI) involves the development of structural and functional abnormalities in the kidneys of patients without renal injury after sepsis. Key factors involved in the pathogenesis of SAKI include inflammatory responses, abnormalities in renal microcirculation, and changes in renal cellular bioenergetics. The overall incidence of SAKI in septic patients is 19% to 23%, while the incidence in patients with septic shock is much higher, ranging from 51% to 66.9%. The excessive release of inflammatory factors in sepsis leads to damage to glomerular capillary endothelial cells and renal tubular epithelial cells, resulting in increased glomerular capillary permeability and decreased glomerular filtration rate (GFR). Moreover, inflammatory factors can induce the release of tissue factors, activating the extrinsic coagulation pathway, leading to the formation of microthrombi in the renal microcirculation. Due to ischemia and hypoxia, the production of ROS in renal tissue increases, leading to increased mitochondrial permeability and decreased mitochondrial membrane potential, resulting in mitochondrial dysfunction and exacerbation of kidney injury.
Studies have shown that MSCs can reduce the incidence of SAKI and alleviate kidney tissue damage. Luo et al. demonstrated that compared to control mice, treatment with 106 MSCs within 3 hours of inducing sepsis in mice reduced the incidence of SAKI. After 24 hours of induction, MSCs reduced the release of inflammatory factors CXC, CCL, and IL-17, and inhibited the migration of neutrophils to the kidneys, improving renal tubular function in septic mice and prolonging survival. Cóndor et al. proved that umbilical cord Wharton’s jelly-derived MSCs inhibit renal cell apoptosis, NF-κB expression, and the release of IL-1 and IL-6, thereby improving GFR and renal tubular function in septic patients. The combination of adipose-derived MSCs (AMSCs) and exendin-4 (a glucagon-like peptide-1 analogue) can reduce renal oxidative stress and fibrosis in sepsis, and the combination of MSCs and melatonin has been shown to significantly reduce NF-κB expression and the release of inflammatory factors. Additionally, MSCs can inhibit thrombosis in the glomerular microcirculation, prevent damage to glomerular endothelial cells, and restore renal function.
⑤Mesenchymal Stem Cells and Septic Encephalopathy. Septic Encephalopathy (SAE) is characterized by altered consciousness, coma, and other changes in awareness. Notably, 10-20% of SAE patients worldwide experience long-term cognitive dysfunction. The pathogenesis of SAE mainly involves neuroinflammation, blood-brain barrier (BBB) damage, cerebral microcirculation disorders, and mitochondrial dysfunction. MSCs can inhibit neuroinflammatory responses and promote the recovery of cerebral microcirculation, thereby improving cognitive dysfunction after sepsis. Studies have shown that MSCs injected via the internal jugular vein and peripheral veins can cross the BBB and settle in damaged areas of the brain. These infiltrating cells have been shown to inhibit the secretion of IL-6, IL-1β, and TNF-α, as well as the proliferation and activation of microglia, thereby weakening the inflammatory response. Tan et al. and Silva et al. demonstrated that MSCs improve cognitive function in septic mice by inhibiting neuroinflammation and peripheral inflammation. Studies have shown that MSCs can secrete various nutritional factors, including brain-derived neurotrophic factor that promotes neuronal differentiation, as well as vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) that promote local angiogenesis and improve blood circulation in brain tissue. MSCs can transfer their mitochondria to damaged cells through membrane channels (TNTs), continuing aerobic respiration and reducing ROS production. Furthermore, they can alleviate mitochondrial dysfunction and reduce oxidative stress. Liu et al. indicated that olfactory mucosa-derived MSCs may promote the expression of UBIAD1, improving mitochondrial function. Cao et al. and Wang et al. demonstrated that MSCs can inhibit the expression of brain iNOS and NADPH oxidase, and MSC-derived exosomes contain antioxidant components such as miRNA that can alleviate oxidative stress-induced damage.
⑥Mesenchymal Stem Cells and Intestinal Dysfunction in Sepsis. Intestinal dysfunction can lead to a high overall incidence and mortality rate of 41.9% in ICU sepsis patients. MSCs can protect against sepsis-induced intestinal dysfunction by weakening intestinal inflammatory responses, enhancing mitochondrial function, and improving microbial diversity. Studies have shown that MSCs can inhibit the production of inflammatory factor TNF-α by regulating dendritic cell function and promote the secretion of anti-inflammatory factor IL-10. Chen et al. and Koliaraki et al. indicated that MSCs can respond to TNF, inhibiting the production of TNF-α and IL-12 while promoting the secretion of IL-4 and IL-10. Parikh et al. and Zheng et al. showed that MSC-derived microvesicles can deliver mfn2 and PGC-1α to endothelial cells, promoting mitochondrial production and directly delivering mitochondria to damaged endothelial cells to improve cellular energy metabolism and reduce oxidative stress-induced damage. Phinney et al. demonstrated that MSCs can promote mitochondrial autophagy. Additionally, MSCs have been shown to promote intestinal mucosal repair and increase the diversity of intestinal microbiota. For example, Valcz et al. showed that MSCs can settle in damaged intestinal mucosa and differentiate into intestinal mesenchymal or epithelial cells. Hayashi et al. also found that MSCs can secrete VEGF and TGF to promote the repair of damaged intestinal mucosa. Furthermore, MSCs can improve the diversity of intestinal microbiota, regulate the secretion of IgA, and maintain intestinal homeostasis.
⑦Mesenchymal Stem Cells and Sepsis-Induced Coagulopathy (SIC). SIC is characterized by enhanced coagulation responses and impaired anticoagulant mechanisms, leading to the production of a large number of microthrombi. The incidence of SIC in sepsis patients is 50-70%, with approximately 35% of patients progressing to disseminated intravascular coagulation globally. The pathogenesis of SIC mainly includes the release of inflammatory mediators, endothelial cell damage, activation of the extrinsic coagulation pathway, and suppression of anticoagulant and fibrinolytic systems. Studies have confirmed that MSCs have effective anti-inflammatory and immunomodulatory functions. For example, Wang et al. and Miao et al. demonstrated that MSCs can inhibit the activity of the NLRP3 inflammasome, reduce levels of IL-1β, IL-6, and TNF-α, and promote the secretion of IL-10. Additionally, MSCs can alleviate endothelial cell damage, thereby improving the anticoagulant function of protein C. Notably, Baudry et al. showed that MSCs pretreated with interferon-γ (IFN-γ) reduced selectin-E levels and increased intercellular adhesion molecule-1 levels, thereby accelerating leukocyte flow in the blood, reducing leukocyte adhesion, and alleviating endothelial cell damage in septic mice. By improving the anticoagulant function of protein C, MSCs can significantly reduce levels of von Willebrand factor and tissue factor in plasma, inhibit the extrinsic coagulation pathway, and reduce thrombin production, thereby improving SIC.
4. The Pathophysiological Relationship Between MSCs and Skeletal Muscle
MSCs have significant directional differentiation capabilities, allowing them to transform into skeletal muscle cells under appropriate conditions. In vitro studies have shown that the transcription factor Pax-3 can induce MSCs to differentiate into myogenic cells, while intracellular domain genes can drive MSCs to differentiate into skeletal muscle cells. Additionally, mechanical traction can stimulate BMSCs to differentiate into skeletal muscle cells. An in vivo study confirmed that embryonic MSCs (eMSC) promote the repair of injured tibialis anterior muscles in mice, with >60% of eMSCs differentiating into skeletal muscle cells. Besides the ability to differentiate into skeletal muscle cells, MSCs can also enhance the functional recovery of injured skeletal muscle. In previous studies, BMSCs isolated from the tibia and femur of transgenic Sprague-Dawley rats expressing green fluorescent protein were cultured and expanded in vitro. After transplanting these BMSCs to the site of skeletal muscle injury, the contraction force of the injured muscle reached nearly pre-injury levels after one month. In contrast, the contraction force of the control group rats only recovered to about 80% of pre-injury levels. Another study indicated that MSCs improve skeletal muscle function in a cell density-dependent manner, with the most significant therapeutic effect observed when the number of transplanted MSCs was 10×106. Notably, the therapeutic effect was not influenced by the timing of MSC transplantation or the sex of the rats. Additionally, MSCs have been shown to promote angiogenesis in skeletal muscle and increase blood flow. In a previous study, compared to the control group, the transplantation of hypoxic MSCs in the hind limbs of mice resulted in a twofold increase in the number of skeletal muscle capillaries and a sevenfold increase in the number of vascular connections and branches. Furthermore, studies have shown that MSCs hold great promise in treating various skeletal muscle diseases, such as Duchenne muscular dystrophy, skeletal muscle denervation atrophy, and traumatic skeletal muscle injuries. These studies provide different avenues for further research on MSCs and the use of MSCs in treating SIMD.
To be continued…