lNTRODUCTlON

Stem cell therapy provides limitless therapeutic options in the field of medicine, which is the direct result of the achievements obtained by the field of regenerative medicine. The therapeutic applications are early in its stages, and the clinical trials are ongoing[1]. Ideal stem cells should have the ability of self-renewal, multilineage capacity, and easily isolated, and cultivation conditions should be simple[2,3]. Mesenchymal stem cells (MSC) have been used abundantly for this purpose[3,4]. MSC have an intricate cell biology and are amenable to being utilized in tissue engineering. They secrete various potent growth factors and cytokines, they have pluripotent differentiation capabilities, and they are abundant in the body including the bone marrow, oral cavity, and adipose tissue[5].

In 2001, Zuk

[6] isolated and defined the stromal vascular fraction of adipose tissue. The stromal vascular fraction contains a mixture of erythrocytes, fibromyoblasts, endothelial cells, smooth muscle cells, pericytes of vascular origin, and fat cells. The stromal vascular fraction can be cultured, forming fibroblast-like cells that are adherent to the culture flask. These cells were originally named preadipocytes[7,8]. However, it has been shown that these cells have mesodermal multipotent differentiation ability, and they are currently called adipose-derived MSC (AD-MSC)[7]. Currently, advancements in tissue engineering and regenerative medicine have shown that these cells can differentiate into cells and tissues of endodermal, mesodermal, and ectodermal origin[1,2]. There are some advantages to using AD-MSC in regenerative medicine. The most important one is the abundance of stem cells in the adipose tissue[9,10]. Adipose tissue contains at least 100 times higher amounts of stem cells when compared to other sources such as the bone marrow[1,11]. Furthermore, the isolation procedure is very simple and efficient[1,2,6,7,12]. Obtaining the fat tissue from individuals is very easy. The proliferative capacity and durability of AD-MSC exceed MSC obtained from other sources[2,13-15].

The isolation procedure is very simple and has been done for a long time[16]. It includes mechanical disruption of the tissue followed by enzymatic digestion and ultracentrifugation (Figure 1). It is cultured in standard cell culture media without the need of a special culture media. During the standard culture of eukaryotic cells 10% (v/v), fetal bovine serum is used. This can lead to certain problems such as immune reactivity and transmission of zoonotic infections[17]. For this reason, platelet-rich plasma can be used as an alternative to fetal bovine serum. Platelet-rich plasma has also been shown to enhance AD-MSC growth

[18].

The heap of feathers that you see here, said she, you must get finished before I come home in the evening, otherwise you shall be set to harder work

There is a uniform pattern of surface marker expression for AD-MSC, which is the presence of CD90, CD73, CD105, and CD44[19,20]. Expression of CD34 and CD49d is highly reserved for AD-MSC and is absent in other MSC types[21]. The secretion profile of AD-MSC includes a wide range of cytokines, chemokines, and growth factors. The effects of the secreted factors are paracrine in their activity. There are factors that promote angiogenesis such as fibroblast growth factor 2, vascular endothelial growth factor, hepatocyte growth factor, and insulin-like growth factor 1[22]. Also, matrix metalloproteinase-3 and matrix metalloproteinase-9 contribute to their proangiogenic activity[23]. Their effect on the system is usually induction of immunoregulatory type changes promoting tissue injury and angiogenesis. The factors that are responsible for the immune effects of AD-MSC are macrophage-colony stimulating factor, granulocyte-colony stimulating factor, interleukin (IL) 6, tumor necrosis factor, and prostaglandin E2[23]. Therefore, there is T helper type 2 polarization of CD4-positive T cells and M2 polarization of the macrophages. All these changes reduce inflammation and increase the wound healing capacity of the tissues[24,25].

Sepsis is an overwhelming inflammatory response to invading microorganisms. The severity of the disease depends on the virulence of the microbial pathogen, amount of toxins secreted by the pathogen, and the physiologic status of the host. The recovery from sepsis depends on the balance between the proinflammatory cytokines and anti-inflammatory mechanisms that counterbalance inflammation[58]. Tumor necrosis factor-α3 and IL-6 are the potent proinflammatory cytokines that have a major role during the pathogenesis of sepsis[59,60]. As our understanding of the physiopathology increases, alternative immunomodulatory therapies are being developed and investigated for clinical use[61].

Most gracious Lord and master, replied the Vizier, near the great Mosque12 lives a man called Selim the learned, who knows every language under the sun

AD-MSC can also be used together with nanoparticle technology to increase the engraftment rates and enhance the efficacy of the AD-MSC in reversal of liver injury and liver fibrosis[43]. Furthermore, the use of liver bioscaffolds has been shown to support the growth of neonatal multilineage progenitor cells into fully functional liver tissue[46]. If stem cells are used during the recellularization process, the results seem to be better when comparted to primary parenchymal cells such as the hepatocytes[43]. Apart from supporting the regenerative process, AD-MSC reduce the ischemia and reperfusion injury during liver surgery and diseases. It has been shown that AD-MSC reduce ischemia reperfusion injury in liver by reduction of various inflammatory cytokines such as IL-1β, IL-6, and tumor necrosis factor[47]. Furthermore, AD-MSC secrete counter regulatory cytokines such as IL-10 and secrete factors such as hepatocyte growth factor and cyclin D1, which are effective in hepatic regeneration[47]. The effects of AD-MSC include immune regulation, reduction of oxidative and inflammatory tissue destruction, and regeneration of the parenchymal cells. The proposed mechanisms of action of AD-MSC are summarized in Figure 2. The clinical trials so far have been successful and have shown a good safety profile of ADMSC in humans. It prevented acute-on-chronic liver failure and improved liver functions in patients with cirrhosis with various etiologies[48-50]. The summary of the preclinical studies and clinical trials are summarized in Supplementary Table 1 and 2.

The aim of the present study was to summarize the current literature in terms of AD-MSC in the cellular therapy for hepatic and biliary regeneration. Also, we briefly summarize the role of AD-MSC in the treatment of septic conditions. We hope this will help the readers to grasp the potential of AD-MSC in the treatment of hepatobiliary diseases.

AD-MSC lN HEPATlC DlSEASE AND REGENERATlON

The immune regulatory and antiapoptotic effects of AD-MSC aid regeneration of the liver and help healing of liver injury caused by viral infections, toxins, and genetic diseases[33,34]. Studies have shown that AD-MSC express liver specific markers even if they are not targeted

[35]. There are many sources for AD-MSC, and each have different biological behavior. Liver falciform ligament-derived ADMSC show higher proliferative capacity and higher embryonic stem cell capabilities[36]. Falciform ligament is readily available during liver surgery and can be used to enhance healing of the tissue following liver surgery. Surgeons have been using falciform ligament flaps to support anastomosis or to fill a gap in the liver following resection for a long time[37]. This may be attributed to the enhanced healing capacity of the stem cells present in the falciform ligament.

The majority of the complications are due to ischemia and reperfusion injury. Ischemia reperfusion injury has adverse effects on both hepatic and biliary regeneration[54,55]. Zhu

[55] reported that warm ischemia times exceeding 20 min were associated with biliary complication and biliary epithelial damage in an experimental model. The cholangiocytes have pluripotent differentiation potential, but it is overwhelmed during ischemia and reperfusion injury[54,55]. MSC therapy may be an alternative or adjunct to conventional therapies for biliary complications. AD-MSC are preferred alternatives for they are easily accessible, and they promote anti-inflammatory mechanisms and regeneration in the tissue, which may be beneficial for biliary regeneration[55,56]. There are limited studies regarding the versatility of AD-MSC in biliary regeneration[47,57]. Abraham

[57] showed that AD-MSC sheets were effective in preventing biliary strictures in duct-to-duct anastomoses. However, the studies were limited regarding the role of AD-MSC in biliary regeneration. Further studies will provide innovative therapeutic options for biliary complications.

In summary, through the paracrine effects of the AD-MSC-derived cytokines, chemokines, and growth factors, AD-MSC stimulate angiogenesis, exert antiapoptotic effects, and recruit other MSC and progenitor cells to the site of injury[27,30,31]. In addition, they stimulate the proliferation and differentiation of the wide range of cells present in the site of injury. They also reduce the reactive oxygen species in the microenvironment and reduce reactive oxygen species-mediated injury to the tissues[27,30,31]. One unique feature of MSC is their ability to fuse with parenchymal cells in the injury site to promote intercellular interactions and exchange cellular macromolecules through the intercellular nanochannels that are formed[27,30-32].

THE ROLE OF AD-MSC lN BlLlARY REGENERATlON

Liver resection and transplantation are among the definitive treatments of life-threatening chronic liver disease and primary/secondary liver tumors. The most frequent complication following liver disease is the biliary complications[51,52]. Some of these complications may even cause mortality in the patients. Stenosis is one of the biliary complications that are observed following hepatobiliary surgery. In major surgeries like living donor liver transplantation, it has been reported to affect 10%-30% of the patients[53]. Treatment of this complication requires repeated procedures, restorative operations, and frequent prolonged hospitalizations.

Experimental studies are abundant showing reduced inflammation, support of hepatic regeneration, and normalization of metabolic derangements in liver failure experimental models. We briefly summarize some of the cornerstone experiments that are present in the literature. Experimental studies have shown that the condition of the host determined the type of differentiation of the AD-MSC. In an experimental model of acute liver failure, it has been shown that AD-MSC showed increased expression of specific markers for hepatocytes[38]. AD-MSC have been shown to be amenable to

targeting to hepatocytes, which can later be used to treat an experimental model of acute liver failure[39]. Transplantation of AD-MSC 24 h before 70% hepatectomy model in rats ameliorated hepatic dysfunction and improved liver regeneration by normalizing the metabolic processes in the liver[40]. Banas

[41] have also reported their results in a carbon tetrachloride treated acute liver failure model. They have shown that treatment with AD-MSC that were preconditioned

ameliorated the liver failure and normalized liver function tests in animals in the treatment arm[41]. AD-MSC given as treatment after the development of acute liver failure have also been shown to be effective in improving liver regeneration and functions[42]. Preconditioning of AD-MSC has resulted in development of functional liver tissue (liver bud) in experimental models[43]. AD-MSC were shown to significantly inhibit the proliferation and activation of hematopoietic stem cells and promote the programmed cell death of hematopoietic stem cells thereby reducing hepatic fibrosis in experimental models[44,45].

Everything went well for a week or a fortnight, and then the woman said, Hark you, husband, this cottage is far too small for us, and the garden and yard are little; the Flounder might just as well have given us a larger house. I should like to live in a great stone castle; go to the Flounder, and tell him to give us a castle. Ah, wife, said the man, the cottage is quite good enough; why should we live in a castle? What! said the woman; just go there, the Flounder can always do that. No, wife, said the man, the Flounder has just given us the cottage, I do not like to go back so soon, it might make him angry. Go, said the woman, he can do it quite easily, and will be glad to do it; just you go to him.

THE ROLE OF AD-MSC lN THE TREATMENT OF SEPSlS

In acute and chronic liver failure, the regenerative capacity of the liver is overwhelmed by the noxious stimuli[26,27]. Therefore, regeneration or repair of the liver is very complicated due to the presence of a variety of parenchymal cells[28]. These cells include the hepatocytes, cholangiocytes, hepatic stellate cells, and immune cells including the Kupffer cells, natural killer cells, natural killer T cells, and eosinophils[28,29].

Currently, MSC are being used for the treatment of sepsis. The majority of these are isolated from the bone marrow, which is not an easy process[62]. AD-MSC have been shown to be effective in endotoxemia-induced sepsis models in rats by reducing apoptosis and the rate of multi-organ failure[63]. The anti-inflammatory action of MSC can be a direct effect through cell-to-cell interaction or may be through paracrine effects of the secreted mediators or secretion of exosomes/microvesicles to the inflammatory microenvironment[62]. MSC have been shown to reduce proinflammatory cytokines and increase cytokines such as IL-10 and induce a regulatory phenotype in the immune cells[64]. Through this mechanism, MSC reduce the amount of macrophage and neutrophil infiltration in target organs such as the lungs, kidneys, and the liver, thus reducing the risk of multiple organ failure[62,65-67]. MSC also increase the phagocytic activity of monocytes in circulation and reduce the effective microbial concentrations[68].

In sepsis or viral pneumonia such as the one seen in coronavirus disease 2019, traditional therapeutic options were insufficient[69]. Bone marrow-derived MSC played an important role for both reduction of inflammatory damage in end-organs and in clearance of microbial agents from the circulation of the patients. The studies regarding the role of AD-MSC in sepsis are not enough, and further studies are needed. The proposed mechanism of action of AD-MSC in hepatobiliary diseases and sepsis are summarized in Figure 2.

And after that they were almost better friends than ever; whenafterwards they returned to the dunes and began telling theiradventures, this was told among the rest. Martin said that Jurgenwas certainly passionate, but a good fellow after all.

CONCLUSlON

There are many unknown points regarding the role of AD-MSC in the treatment of hepatobiliary diseases. However, the results of preclinical studies and limited clinical trials are promising. It seems to be a good alternative treatment to bridge acute or acute-on-chronic liver failure until a definitive liver transplantation can be performed. Furthermore, it may promote the wound-healing process preventing many complications in the biliary tract following major liver surgeries.

The utility of AD-MSC in the treatment of hepatobiliary disease and sepsis is relatively new. Brief reports are showing the efficacy of AD-MSC in controlling inflammation and regenerating parenchymal tissue. However, there is not a firmly established protocol. The dose and dosing intervals of the allogenic AD-MSC transplantation requires further research for establishing universal protocols. Furthermore, the role of targeted or genetically modified AD-MSC are unknown. Bioscaffolds may also provide modeling of the tissue and providing precursors for the liver and biliary tract. Combination of AD-MSC with nanoparticles for potentiating the anti-inflammatory response will be an important area of research in the future. Therefore, further research is needed to guide physicians for future innovative clinical applications.

FOOTNOTES

Satilmis B and Sahin TT designed and wrote the paper; Cicek E and Cicek GS performed the literature analysis; Akbulut AS and Y?lmaz S reviewed the paper.

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

In 1945, there was a young boy of 14 in a concentration camp（）. He was tall, thin but had a bright smile. Every day, a young girl came by on the other side of the fence. She noticed the boy and asked him if he spoke1 Polish, and he said yes. She said he d looked hungry, and he said he was. She then reached in her pocket and gave him her apple. He thanked her and she went on her way. The next day, she came by again, bringing with her another apple which she gave him. Each day, she walked by the outside of the fence, hoping to see him, and when she did, she happily handed him an apple in exchange for（） conversation.

Turkey

One night, the boy really missed the girl. When he called her however, the girl s cell phone was off because she was already asleep. The next day, the boy asked the girl to leave her cell phone on at night because when he needed to find her and could not, he would be worried.

Basri Satilmis 0000-0002-2538-5774; Gizem Selen Cicek 0000-0003-2267-5335; Egemen Cicek 0000-0003-2691-7418; Sami Akbulut 0000-0002-6864-7711; Tevfik Tolga Sahin 0000-0002-9132-6115; Sezai Yilmaz 0000-0002-8044-0297.

Liu JH

They died almost at the same time, leaving their kingdom to the eldest4 of their children, and commending their youngest son, Prince Narcissus, to the care of the Fairy Melinette

Filipodia

Liu JH

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