Transition of clinical and basic studies on liver cirrhosis treatment using cells to seek the best treatment

Abstract

The liver is a highly regenerative organ; however, its regeneration potential is reduced by chronic inflammation with fibrosis accumulation, leading to cirrhosis. With an aim to tackle liver cirrhosis, a life-threatening disease, trials of autologous bone marrow cell infusion (ABMi) therapy started in 2003. Clinical studies revealed that ABMi attenuated liver fibrosis and improved liver function in some patients; however, this therapy has some limitations such as the need of general anesthesia. Following ABMi therapy, studies have focused on specific cells such as mesenchymal stromal cells (MSCs) from a variety of tissues such as bone marrow, adipose tissue, and umbilical cord tissues. Particularly, studies have focused on gaining mechanistic insights into MSC distribution and effects on immune cells, especially macrophages. Several basic studies have reported the use of MSCs for liver cirrhosis models, while a number of clinical studies have used autologous and allogeneic MSCs; however, there are only a few reports on the obvious substantial effect of MSCs in clinical studies. Since then, studies have analyzed and identified the important signals or components in MSCs that regulate immune cells, such as macrophages, under cirrhotic conditions and have revealed that MSC-derived exosomes are key regulators. Researchers are still seeking the best approach and filling the gap between basic and clinical studies to treat liver cirrhosis. This paper highlights the timeline of basic and clinical studies analyzing ABMi and MSC therapies for cirrhosis and the scope for future studies and therapy.

Increased serum extracellular vesicle miR-144-3p and miR-486a-3p in a mouse model of adipose tissue regeneration promote hepatocyte proliferation by targeting Txnip

“…MSCs are promising cells for the regeneration of damaged tissues owing to their anti-apoptotic, cell proliferative, and immunoregulatory properties [ 19 ]. Liver cirrhosis is a life-threatening condition with decreased viable hepatocytes, and since there is no effective treatment option other than liver transplantation, regenerative therapy using MSCs has been vigorously investigated for this disease [ 22 , 30 ]. While animal studies have achieved compelling results of MSC administration for liver regeneration, the efficacy observed in current clinical studies appears to be modest and lower than expected [ 22 ].…”

“…Liver cirrhosis is a life-threatening condition with decreased viable hepatocytes, and since there is no effective treatment option other than liver transplantation, regenerative therapy using MSCs has been vigorously investigated for this disease [ 22 , 30 ]. While animal studies have achieved compelling results of MSC administration for liver regeneration, the efficacy observed in current clinical studies appears to be modest and lower than expected [ 22 ]. The reasons for this are still unknown, and to achieve therapeutic applications, it seems necessary to identify the molecules responsible for the regenerative effects and to elucidate the precise mechanism.…”

“…Because ASPCs are relatively easy to isolate, they are expected to be applied to regenerative therapy for various diseases including liver cirrhosis. Many studies have investigated EV-miRNAs secreted from ASPCs in vitro [ 22 ]; however, little is known about EV-miRNAs secreted in vivo . This is because ASPCs are minor populations in adipose tissue, making it difficult to analyze EV-miRNAs secreted from ASPCs separately from other cells.…”

Mesenchymal Stem Cell Immunomodulation: A Novel Intervention Mechanism in Cardiovascular Disease

“…However, the stirred bioreactor preparation method may lead to cells destruction and thus affect the immunomodulatory activity of MSCs. MSCs exert immune regulation mostly through direct cell-to-cell contact, for example, promoting phenotypic transformation of macrophages through direct cell-to-cell contact ( Terai et al, 2021 ) or by releasing cytokines through paracrine effect, such as secretion, IDO, TGF-β, and PGE2 ( Di Trapani et al, 2016 ). It can function as an immunomodulatory agent by secreting exosomes, such as the inhibition of IL-6 and TNF-α secretion through exosomes, thereby regulating the inflammatory microenvironment ( Lu et al, 2021 ).…”

Mesenchymal stem cells-based therapy in liver diseases

“…Some researchers have suggested that MSCs injected into the body are mostly trapped in the lungs, but these MSCs can provide signals to liver macrophages as a way to reduce liver fibrosis [ 519 ]. MSCs are dependent on IL-6 and PGE2, among others, to promote the polarization of macrophages toward the anti-inflammatory M2 phenotype [ 520 , 521 ].…”