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Review
. 2023 Oct 16;24(20):15212.
doi: 10.3390/ijms242015212.

The Crosstalk between Mesenchymal Stromal/Stem Cells and Hepatocytes in Homeostasis and under Stress

Irina V Kholodenko  1 , Roman V Kholodenko  2 , Konstantin N Yarygin  1
Affiliations
Review

The Crosstalk between Mesenchymal Stromal/Stem Cells and Hepatocytes in Homeostasis and under Stress

Irina V Kholodenko et al. Int J Mol Sci. .

Abstract

Liver diseases, characterized by high morbidity and mortality, represent a substantial medical problem globally. The current therapeutic approaches are mainly aimed at reducing symptoms and slowing down the progression of the diseases. Organ transplantation remains the only effective treatment method in cases of severe liver pathology. In this regard, the development of new effective approaches aimed at stimulating liver regeneration, both by activation of the organ's own resources or by different therapeutic agents that trigger regeneration, does not cease to be relevant. To date, many systematic reviews and meta-analyses have been published confirming the effectiveness of mesenchymal stromal cell (MSC) transplantation in the treatment of liver diseases of various severities and etiologies. However, despite the successful use of MSCs in clinical practice and the promising therapeutic results in animal models of liver diseases, the mechanisms of their protective and regenerative action remain poorly understood. Specifically, data about the molecular agents produced by these cells and mediating their therapeutic action are fragmentary and often contradictory. Since MSCs or MSC-like cells are found in all tissues and organs, it is likely that many key intercellular interactions within the tissue niches are dependent on MSCs. In this context, it is essential to understand the mechanisms underlying communication between MSCs and differentiated parenchymal cells of each particular tissue. This is important both from the perspective of basic science and for the development of therapeutic approaches involving the modulation of the activity of resident MSCs. With regard to the liver, the research is concentrated on the intercommunication between MSCs and hepatocytes under normal conditions and during the development of the pathological process. The goals of this review were to identify the key factors mediating the crosstalk between MSCs and hepatocytes and determine the possible mechanisms of interaction of the two cell types under normal and stressful conditions. The analysis of the hepatocyte-MSC interaction showed that MSCs carry out chaperone-like functions, including the synthesis of the supportive extracellular matrix proteins; prevention of apoptosis, pyroptosis, and ferroptosis; support of regeneration; elimination of lipotoxicity and ER stress; promotion of antioxidant effects; and donation of mitochondria. The underlying mechanisms suggest very close interdependence, including even direct cytoplasm and organelle exchange.

Keywords: apoptosis; cell-to-cell communication; ferroptosis; hepatocytes; lipotoxicity; liver diseases; mesenchymal stem cells; mitochondrial transfer; pyroptosis; regeneration.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The role of MSCs in the formation of liver organoids. MSCs provide the contractile force for the formation of the heterotypic hepatic organoids and enhance the viability of hepatocytes either through direct contact between hepatocytes and MSCs or via paracrine factors contributing to the proliferation and maintenance of the functional activity of hepatocytes. MSCs produce ECM proteins, facilitating the adhesion of hepatocytes, and enhance the expression of β-integrin by hepatocytes, contributing to the transition of hepatocytes to the S phase of the cell cycle. Within the organoids, MSCs are able to differentiate into endotheliocytes, which form structures similar to a capillary network.
Figure 2
Figure 2
Reciprocal effects of hepatocytes and MSCs in direct co-cultures. MSCs produce hepatotrophic factors, including HGF, IL-6, and PAI-1, while their expression, in turn, is enhanced by hepatocytes. Hepatotrophic factors enhance the survival and proliferation of hepatocytes and improve their functional activity, as witnessed by heightened albumin production and ureagenesis. MSCs secrete TGF-β, which, through autocrine regulation, stimulates the production of ECM proteins, thereby facilitating hepatocyte adhesion and promoting their proliferation. On the other hand, TNF-α secreted by primary hepatocytes can induce their own apoptosis also via autocrine mechanisms. MSCs significantly reduce the expression of TNF-α by hepatocytes, thereby protecting hepatocytes from cell death. HGF—hepatocyte growth factor; IL-6—interleukin 6; PAI-1—plasminogen activator inhibitor-1; TNF-α—tumor necrosis factor α; TGF-β—trans-forming growth factor β; ECM—extracellular matrix.
Figure 3
Figure 3
Mechanisms of the anti-apoptotic action of MSCs in the hepatocyte–MSC co-cultures. MSCs inhibit stress-induced apoptosis and cell cycle arrest in hepatocytes through the secretion of the hepatotrophic factors IL-6, HGF, and PGE2, as well as through the production of the miRNA-loaded exosomes. In stressed hepatocytes, MSCs downregulate the expression of the proapoptotic proteins Bax, cleaved caspase 3, and BID and upregulate the expression of the anti-apoptotic protein Bcl-2. MSC-produced PGE2 activates two interconnected signaling pathways involved in liver regeneration. YAP activation is mediated through p-CREB and leads to the suppression of PTEN by miR-29a-3p and subsequent activation of mTOR signaling, ultimately leading to the inhibition of apoptosis and an increase in hepatocyte proliferation. MSCs reduce the miR143 level in hepatocytes subjected to oxidative stress and, accordingly, increase the levels of HK2 and ADRB1. This results in decreased oxidative phosphorylation and a switch to glycolysis, ultimately leading to hepatocyte proliferation and protection from apoptosis. MSCs attenuate damage caused by oxidative stress in hepatocytes by inhibiting miR-486-5p, upregulating PIM1, and blocking TGF-β/Smad signaling. MSCs activate PTEN/AKT signaling pathway in damaged hepatocytes by upregulating miR-20a-5p, thus enhancing their proliferation. MSC-derived exosomal miR-124 promoted liver regeneration by enhancing hepatocyte proliferation through the downregulation of Foxg1. IL-6—interleukin-6; HGF—hepatocyte growth factor; PGE2—prostaglandin E2; YAP—Yes-associated protein; p-CREB—p-cAMP-responsive element binding protein; PTEN—phosphatase and tensin homolog; mTOR—mammalian target of rapamycin; HK2—hexokinase 2; ADRB1—beta-1-adrenergic receptor; PIM1—proviral integration site for Moloney murine leukemia virus kinase 1; TGF-β—transforming growth factor-β.
Figure 4
Figure 4
The PRL-1-dependent mechanism of hepatoprotective action of MSCs. Normal hepatocytes and MSCs both express PRL-1. After treatment of primary rat hepatocytes with lithocholic acid, the level of PRL-1 expression decreased. Co-cultivation with MSCs resulted in the restoration of PRL-1 expression in hepatocytes. MSC homing was regulated by RhoA-mediated ROCK1 signaling. PRL-1 produced by hepatocytes acted as a chemokine for MSCs due to increased MMP-2 expression in MSCs. On the other side, PRL-1 produced by MSCs increased anaerobic mitochondrial metabolism in damaged hepatocytes, decreasing cytoplasmic lactate and increasing mitochondrial lactate, which ultimately led to increased ATP synthesis and hepatocyte repair. PRL-1—phosphatase of regenerating liver; MMP-2—matrix metalloproteinase 2; ATP—adenosine triphosphate; RhoA—Ras homolog family member A; ROCK1—Rho-associated coiled-coil-containing protein kinase 1.
Figure 5
Figure 5
Hepatocyte protection from ferroptosis mediated by MSC or MSC derivatives. MSC-derived exosomes loaded with miR-204-5p inhibit ferroptosis by reducing Fe2+ intracellular overload and ROS and MDA levels and by upregulating the expression of GPX4, a protective enzyme that prevents ferroptosis. Also, MSC-derived exosomes induce the stabilization of SLC7A11 via increased expression of CD44 and OTUB1. Thus, MSC may prevent hepatocyte ferroptosis by activation of the antioxidant system.
Figure 6
Figure 6
Hepatocyte protection from pyroptosis by MSC or MSC derivatives. MSCs reduce NLRP3-caspase 1 inflammasomes in stressed hepatocytes via the expression of the IL-10 anti-inflammatory cytokine. Also, MSC-derived exosomes reduce the expression of the markers of pyroptosis NLRP3, GSDMD, caspase 1, IL-1β, and IL-18 and the suppression of hepatocyte pyroptosis, probably due to the reduction in inflammation. NLRP3—NLR family pyrin domain containing 3; IL-10—interleukin-10; GSDMD—gasdermin D; IL-1β—interleukin-1β; IL-18—interleukin-18.
Figure 7
Figure 7
Reciprocal mitochondrial transfer between stressed hepatocytes and MSCs. MSCs prevent hepatocyte cell death by donating their mitochondria to hepatocytes. This process promotes the recovery of lipid utilization, averts lipid accumulation, stimulates the biogenesis of mitochondria, and increases ATP production.
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