Therapeutic properties of Stem Cell-Derived Extracellular Vesicles in various tissue injury.

Introduction: Stem cell (SC) is the type of the cell having the potency to form any kind of cells and tissues in the body. Due to this totipotent property, it is widely used in regenerative medicine. In humans, stem cells are majorly found in embryonic tissues, placental tissues, human umbilical cord (huSC), bone marrow (BMSC), peripheral blood, adipose tissue (AdSC). Most common stem cells are mesenchymal stem cell (MSC) that is present in the circulatory system. There is also a group of stem cells which are produced by bioengineering methodology known as an induced pluripotent stem cell. They are also capable of getting transformed into any cell type. Presence of stem cells allows tissue homeostasis. 

Extracellular vesicles (EV) are known for the communication between the plasma membrane of the cell and cytosolic biomolecule. Exosomes (EX) and microvesicles (MV) are two types of EV. Both facilitate communication between the cells in close as well as distant proximity. They are released by the healthy cells in response to interacting with the recipient cells by binding to receptors, endosomal uptake, fusing with the cell membrane, by translocation of protein through cellular channels. Exosomes are released by the immune cells, and they act as antigen-presenting vesicles to suppress inflammation. It acts as both anti-inflammatory and pro-inflammatory factors. It releases cytokines that regulate the immune response. It is also found to be involved in myelin sheath formation in the nerve cell. 

Taking into consideration their role in treating different type of cellular defects, research has found that stem cells are the most common source of EV producing cells. From the above source of stem cell, they could be extracted and transformed into EV cells under in-vitro conditions. Recent research is more focused on treating different damage tissue by extracellular vesicles derived different stem cell source in mice models. Stem cells are reprogrammed to EVs by using different growth factors and transcription molecule. Stem cell derived EVs replace damaged tissue by new cell type particular to the tissue region.

Stem cell derived EV in the treatment of damaged tissue:

Nerve cell damage repair: In brain trauma, the nerve cell gets damaged. In such case exosomes derived from adipose tissue mesenchymal stem cells increases the number of nerve cells, reduce inflammation, and improves cognitive function. They also play a critical role in improving condition in Alzheimer's disease. In this condition, there is an accumulation of Aβ protein that forms the amyloid structure and impairs cognitive function. Adipose tissue mesenchymal stem cell exosomes (AdMSC-EXs), inhibit Aβ protein by transporting Aβ protease that inhibits amyloid formation. In spinal cord injury, BMSC-EV inhibits nerve cell apoptosis, neuroinflammatory response and enhances motor function. 

Blood vessel repair: In heart disease, the cardiac muscle cells and the blood vessels get damaged. SC-EVs have immense application in treating myocardial infarction. They promote cardiac blood flow and reduced infarction size and thus recovers cardiac function. SC-EVs encapsulate microRNA, and they repair cardiac cell by angiogenesis. They reduce the inflammatory responses in cardiovascular diseases by activating macrophages and neutrophils and recruiting them to the disease site. 

Lung, Liver and Eye damage: BMSC-EVs are involved in promoting the vascular system of the lungs by improving inflammation and delivering protein angiopoietin-1 messenger RNAs that leads to the formation of new blood vessels in the lungs. In acute lung injury, these BMSC-EVs maintained the integrity of microvascular epithelial cells that eventually reduced lung inflammation. When human umbilical cord-derived stem cells (hucMSC-EXs) is treated with vascular endothelial growth factor, mediates the therapeutics effect of EV in lung injury. 

BMSC-EVs migrate to the liver cells when administered, protects the liver against failure by regulating inflammatory response and reduce oxidative stress. 

In hyperglycemic condition, injecting human cord mesenchymal stem cell derived exosomes (hucMSC-EXs) and retinal endothelial cells down-regulates the expression of interleukin receptors reducing retinal inflammation and improve retinal laser injury and also preserved retinal vascular blood flow.  

Diabetes: In type 2 diabetes intravenous infusion of hucMSC-EXs showed decreased blood glucose level and promoted the cellular uptake of glucose and glycogen storage. It activated the insulin signalling pathway and relieved the destroyed beta-pancreatic cells. Urinary stem cell-derived exosomes showed a decreased level of urinary albumin, inhibited the apoptosis of cells in the renal tubules and promoted the growth of endothelial cells in glomerular. BMSC-EXs transported mRNAs of the insulin-like growth factor 1 (IGF-1) receptor to renal tubular epithelial cells in vitro, which increased IGF-1 receptor sensitivity to local IGF-1 and treated kidney tubule injury.

Thus SC-EVs use in therapeutics has made progress in regenerative medicine. Ongoing research is focused on making advancement in regenerative medicine by optimizing EV-production under in-vitro conditions, working on improving yield, quality and quantity, and their therapeutic efficacy to be able to use in humans.