How Stem Cells Treat Liver Fibrosis

Liver fibrosis is a chronic liver disease characterized by the accumulation of extracellular matrix (ECM) proteins that, if left unchecked, may lead to cirrhosis or hepatocellular carcinoma .

Hepatocyte injury, inflammatory response, and apoptosis can be caused by various causes, all of which can induce liver fibrosis. Current treatments for liver fibrosis include antiviral drugs and immunosuppressive therapies, but their efficacy is limited.

Although the liver has a strong regenerative capacity, aging is a huge disadvantage to liver regeneration.

Mesenchymal stem cells (MSC) can regulate the immune response, promote liver regeneration, maintain the quality of liver cell mitochondria by regulating the immune system and promoting mitophagy, thereby providing protection for the liver.

In addition, mesenchymal stem cells can also inhibit the activation of hepatic stellate cells ( HSC ) that leads to disease development , so mesenchymal stem cells have become an effective therapy for the treatment of liver fibrosis .

Autophagy is an important cellular self-degradation process that is critical for maintaining homeostasis and resisting nutritional, metabolic, and infection-mediated stresses. In addition, aging-related autophagy damage can cause mesenchymal stem cells to decline in number and function.

So, what is the relationship between the anti-fibrotic properties of mesenchymal stem cells and autophagy and aging?

Researchers from Chengdu University of Traditional Chinese Medicine and their collaborators published a review titled " Unlocking the potential of Mesenchymal stem cells in liver Fibrosis: Insights into the impact of autophagy and aging " in International Immunpharmacology , summarizing the mesenchymal Recent advances in autophagy and aging aspects of stem cells in the treatment of liver fibrosis .

—Barrow mesenchymal stem cells: an all- rounder in the treatment of liver fibrosis—

Liver fibrosis is essentially a wound healing process that involves several key events, such as hepatic stellate cell activation, excessive extracellular matrix deposition, immune cell infiltration, and hepatocyte senescence.

Treatment based on bone marrow mesenchymal stem cells is very promising in the treatment of liver fibrosis because these cells have a certain role in the above pathophysiological problems.

First, mesenchymal stem cells can reduce the number of activated hepatic stellate cells expressing α-smooth muscle actin (αSMA) and reduce extracellular matrix deposition, thereby exerting an anti-fibrotic effect.

Experiments have shown that in mouse liver fibrosis models, the mesenchymal stem cell secretome significantly inhibits the expression of multiple fibrosis factors. Topical administration of mesenchymal stem cells improves liver fibrosis by reducing fibroblast activation and collagen deposition.

In addition, MFGE8 secreted by mesenchymal stem cells is a strong inhibitor of hepatic stellate cell activation and can also reduce extracellular matrix deposition.

Studies have shown that mesenchymal stem cells can inhibit excessive deposition of extracellular matrix, weaken inflammatory and immune responses, and promote hepatocyte regeneration during liver fibrosis.

There is growing evidence that the anti-inflammatory properties of mesenchymal stem cells are also crucial . Mesenchymal stem cells can reduce liver damage by reducing the number of CD4+ T cells, weakening their activation, and promoting the production of regulatory dendritic cells (DC) and Treg cells.

However, the effectiveness of mesenchymal stem cell therapy relies on maintaining appropriate autophagy levels, and age-related impairment of autophagy can lead to a decrease in mesenchymal stem cell number and function, thereby compromising autophagy levels.

—Autophagy : the balancer of bone marrow mesenchymal stem cells—

Precisely calibrated autophagy machinery controls the nutritional, immunomodulatory, and osteoinductive properties of mesenchymal stem cells.

Reduced autophagy will lead to mesenchymal stem cell senescence, and excessive autophagy will shorten the lifespan of mesenchymal stem cells . In addition, autophagy also protects the mesenchymal stem cell pool throughout the aging process and also plays a certain role in restoring the characteristics of aging mesenchymal stem cells.

Autophagy contains a series of indispensable proteins, including Atg5, Atg7, Beclin-1, and p62, which can affect the metabolism and function of mesenchymal stem cells. Therefore, autophagy is crucial for mesenchymal stem cells to exert their therapeutic effects.

The therapeutic efficacy of mesenchymal stem cells relies on appropriate autophagy levels, as good autophagy levels can improve the proliferation process. In the treatment of liver fibrosis, manipulating autophagy of mesenchymal stem cells may be an effective strategy to improve their anti-fibrotic potential.

—Autophagy and aging in liver fibrosis—

Repeated and sustained liver injury leads to hepatocyte death, triggers an irreversible progressive wound healing response, abnormal accumulation of extracellular matrix components, and ultimately leads to severe fibrosis.

Autophagy may play a protective role in preventing fibrosis by removing damaged extracellular matrix proteins.

Autophagy also plays a crucial role in hepatic stellate cell differentiation. In mice, inhibition of hepatic stellate cell activation and autophagy reduces fibrotic responses.

Activated hepatic stellate cells can proliferate and produce extracellular matrix, while secreting senescence-associated secretory phenotype (SASP), promoting degradation of the extracellular matrix and promoting its return to a quiescent state.

For senescent hepatocytes, SASP can induce senescence in adjacent normal hepatocytes, thereby further activating hepatic stellate cells .

For senescent cholangiocytes, SASP can recruit myofibroblasts and macrophages to promote hepatocyte aging, ultimately leading to liver fibrosis.

The role of cellular senescence in liver fibrosis

—Autophagy and aging of bone marrow mesenchymal stem cells—

Basal levels of autophagy are critical for mesenchymal stem cells to maintain biological effector functions.

In aging mesenchymal stem cells, basal autophagy is increased as it is required to maintain their self-renewal and regenerative capabilities. On the contrary, impaired and reduced autophagy, or excessive autophagy, will promote the senescence of mesenchymal stem cells.

During replicative aging, MDC (a specific marker of autophagic vesicles) and the autophagy-related effectors Atg12 and LC3-I/II mediated by p53 are increased in mesenchymal stem cells.

Hepatic stellate cells are liver-resident mesenchymal stem cells. In an aging liver, hepatic stellate cells also become senescent and release less hepatocyte growth factors, which is detrimental to the regenerative response in the liver.

In aging mesenchymal stem cells, the secretion of pro-inflammatory SASP factors increases , including IL6, MCP1, IL8, IL1α, Groβ, and CCL4. Furthermore, the immunomodulatory properties of senescent mesenchymal stem cells are also significantly reduced.

Aged bone marrow mesenchymal stem cells release SASP factors, which spread inflammatory signals to adjacent hematopoietic stem cells and progenitor cells in a paracrine manner, thereby reducing their clonal capacity and causing more extensive effects of aging.

Aging reduces the stem cell pool, reduces regenerative capacity, and impairs hepatic stellate cell function . In summary, there is a close link between aging and mesenchymal stem cell properties, with aging weakening the repair potential of mesenchymal stem cells and leading to accelerated tissue damage.

The role of autophagy in MSC senescence

In summary, autophagy plays the role of both promoter and inhibitor in the aging of mesenchymal stem cells , and the basal level of autophagy helps maintain the characteristics of mesenchymal stem cells.

In aging mesenchymal stem cells, increased autophagy can slow down metabolism and enhance the ability of mesenchymal stem cells to resist aging. Reduced autophagy may lead to extensive accumulation of toxic substances and damage to mitochondria, exacerbating inflammatory responses and cell damage, and ultimately accelerating aging.

Therefore, understanding the relationship between autophagy and mesenchymal stem cell senescence can help develop new liver fibrosis therapies.