![]() While MSC have the ability to differentiate and can thereby contribute to hepatic epithelial replacement, many other observed effects of MSC can be attributed to paracrine effects that occur as a result of factors that are secreted or released from the cells. The limited half-life of transplanted cells and potential tumorigenic and other risks of MSC have further prompted development of acellular therapies. Furthermore, allogeneic MSC could be eliminated by CD8 + cytotoxic T lymphocytes, whereas transplanted autologous or allogeneic MSC could be eliminated by natural killer (NK) cells. Allogeneic MSC that engraft within target organs can lose their immune privileged status due to the surface expression of major histocompatibility complex class II as well as CD86, and be eliminated from the body due to the generation of anti-donor MSC antibodies. Elimination by adaptive immune cells and the loss of their immune privileged status can both contribute to the short half-life of transplanted MSC. Systemically delivered allogeneic MSC tend to accumulate in the lungs within the first 24 h of transplant those that escape entrapment by the lungs sequester within the liver and spleen. The half-life of transplanted MSC may be inadequate for tissue regeneration by MSC differentiation. The underlying concerns of the potential for tumor formation or differentiation into undesirable cell types have hindered the adoption and use of MSC-based therapeutic approaches, even though these risks remain unsubstantiated. These include the potential for aberrant differentiation, tumor formation and low engraftment. Moreover, MSC are capable of releasing proteins and extracellular vesicles (EV) that have been shown to directly modulate liver injury in different models.Äespite their beneficial properties, there are several limitations to the use of MSC as cellular therapies. Furthermore, through the release of anti-inflammatory cytokines and factors, MSC have immunomodulatory effects on both the innate and adaptive immune systems (, 8]). Their capacity for diapedesis across the endothelium is enabled by the cell surface expression of chemokine receptors, adhesion antigens that ensure cell binding to the endothelium wall, and the expression and subsequent release of matrix metalloproteases (MMP) and other proteolytic enzymes. Next, they have migratory and homing capabilities that enable their sequestration into regions of injury. First, MSC have the capacity for multi-lineage differentiation into a myriad of different cell types. MSC have several characteristics that contribute to their reparative and regenerative properties. The secretome from MSC that are resident in the liver or MSC that are recruited to the liver could have functional effects. MSC from sites other than the liver such as the bone marrow can also be recruited to the liver when there is injury present. Liver MSC are elongated and spindle-shaped, and express stem-cell markers such as vimentin and MSC markers such as CD90, but not markers of hematopoietic stem cells such as CD45, or markers of other liver progenitor cells such as CK19. MSC are cells with differentiation capability which were first isolated from bone marrow but can be derived from perivascular cells from a number of tissues, including the liver. Regenerative therapies involving the use of MSC are a promising therapeutic approach for reducing liver injury, modulating the immune response to injury, and enhancing repair and regeneration of hepatic epithelia. Therapies that can repair or regenerate the liver in the setting of persistent injury or inflammation are needed to avoid reliance on replacement therapies such as transplantation which are not a viable option for many patients. ![]() In the absence of any effective therapies to ameliorate or reverse fibrotic changes, the only therapy currently available to those with advanced chronic liver disease is hepatic replacement with a liver transplant. The accumulation of fibrotic tissue may not be fully reversible, and can be progressive. If the injury or inflammation persists and the responses are unchecked, hepatic fibrosis can develop. ![]() Exposure to such insults can elicit tissue inflammation as well as result in innate and adaptive immune responses that could also directly contribute to further injury. Acute liver injury can occur as a consequence of ischemic, toxic–metabolic, cytotoxic or other insults. An underlying pathophysiological feature in many diseases affecting the liver, irrespective of the etiology, is the presence of hepatic injury and inflammation. ![]()
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