MSC-CM and its potential in liver diseases treatments

The global incidence rates of liver cancer have been referenced from the GLOBOCAN 2020 database, comprising 185 countries with figures calculated per 100,000 people per year. In 2020, healthcare professionals diagnosed an estimated 905,700 cases of liver cancer globally, leading to 830,200 deaths [1,2]. Liver cancer ranks among the top three causes of cancer-related deaths in 46 countries and is among the leading five causes of cancer-related deaths in 90 countries [3]. The incidence and mortality rates are higher in males across all regions worldwide. New liver cancer cases per year are predicted to increase by 55.0% from 2020 to 2040, with an estimated 1.4 million diagnosed cases in 2040. It is projected that 1.3 million individuals may die from liver cancer in 2040 (an increase of 56.4% compared to 2020) [2]. The burden of liver cancer is widespread globally. Preventable causes of liver cancer could be controlled with prioritized efforts, and the predicted increase in cases may escalate the demand for resources to manage patient care and affect the quality of life.

Common Liver Disease Treatment Methods

One of the most effective treatments for acute liver failure (ALF) patients is liver transplantation, considered a standard approach for their treatment (Figure 1). This method involves a surgical process to replace a diseased liver with a healthy liver from a donor[4]. However, due to a shortage of donor livers, the cost of surgery implementation, and particularly immune-related barriers, significantly affects post-liver transplant patients [5]. The study reveals a significant cost involved in liver transplantation. Researchers estimated that approximately a decade ago, a liver transplant in the United States cost an average of USD 163,438, but recent estimates show it has risen to around USD 878,400. Patient characteristics, disease attributes, hospital quality, the healthcare service provider team, and varied surgical methods contribute to cost variations. Recently, scientists have highlighted that MSC transplantation is a promising therapy for liver damage. However, concerns persist regarding the use of MSCs in treatment and unclear mechanisms for liver disease treatment [7].

Figure 1: Patient receiving a liver transplant from a donor

Potential of MSC-CM in Liver Disease Treatment

Mesenchymal stem cells (MSCs) are emerging as potential candidates for treating various diseases due to their regenerative potential. However, the treatment mechanism and potential risks of using MSCs remain a significant challenge in research. To address the risks involved in using MSCs for treatment, scientists have suggested a cell-free therapy that involves nourishing MSCs with the secretome from stem cells, known as conditioned media (CM), which can treat various conditions, including liver damage like liver failure and cirrhosis [8]. Several causes lead to liver damage, such as hepatitis viruses A, B, C, or prolonged cirrhosis. Among these, the development of acute-on-chronic liver failure (ACLF) is the most important cause of patient mortality. ACLF, which is characterised by increased systemic inflammation and reduced liver cell regeneration, leads to multi-organ failure [9]. Therefore, MSC-CM, comprising immune-regulating factors and stimulating liver cell proliferation, may improve the patient’s liver condition [10].

In vitro cultured MSC-conditioned media primarily contains secretome components, including soluble proteins and extracellular vesicles (EVs). They possess regenerative properties by effectively modulating the immune system, improving liver damage, and reducing fibrosis (Figure 2). The CM includes soluble proteins like cytokines or chemokines secreted by MSCs, capable of directly or indirectly impacting immune cells in damaged tissues. Specifically, growth factors and cytokines in the secretome, such as transforming growth factor-beta (TGF-β), hepatocyte growth factor (HGF), interleukin-10 (IL-10), and prostaglandin E2 (PGE2) [11], can regulate signalling, stimulate liver cell proliferation, and reduce fibrosis. Besides soluble proteins, extracellular vesicles (EVs) in CM also have immune-modulating abilities by activating various signaling pathways (STAT3, Bcl2) [12]. In both in vitro and in vivo models, CM from MSCs derived from umbilical cords showed the ability to decrease natural cell death in a liver failure model, simultaneously reducing the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum [13].

Figure 2: Mechanisms of therapeutic efficacy. The secretome can have a wide range of therapeutically beneficial effects, such as immune modulation, injury amelioration, and fibrosis attenuation. [14]

Regarding future development potential, CM containing MSC secretome presents a new and compelling option for treatment applications as a regenerative therapy for liver damage, cirrhosis, or liver failure. Although no clinical trials currently utilise MSC-CM in liver disease treatment, the positive data and outcomes obtained from preclinical in vitro and in vivo studies highlight the necessity of researching, evaluating, and using them in clinical settings.

References:

1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F: Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021, 71(3):209-249.
2. Rumgay H, Arnold M, Ferlay J, Lesi O, Cabasag CJ, Vignat J, Laversanne M, McGlynn KA, Soerjomataram I: Global burden of primary liver cancer in 2020 and predictions to 2040. J Hepatol 2022, 77(6):1598-1606.
3. Arnold M, Abnet CC, Neale RE, Vignat J, Giovannucci EL, McGlynn KA, Bray F: Global Burden of 5 Major Types of Gastrointestinal Cancer. Gastroenterology 2020, 159(1):335-349 e315.
4. Shi M, Zhang Z, Xu R, Lin H, Fu J, Zou Z, Zhang A, Shi J, Chen L, Lv SJSctm: Human mesenchymal stem cell transfusion is safe and improves liver function in acute-on-chronic liver failure patients. 2012, 1(10):725-731.
5. Lee C-W, Chen Y-F, Wu H-H, Lee OKJG: Historical perspectives and advances in mesenchymal stem cell research for the treatment of liver diseases. 2018, 154(1):46-56.
6. van der Hilst CS, Ijtsma AJ, Slooff MJ, Tenvergert EM: Cost of liver transplantation: a systematic review and meta-analysis comparing the United States with other OECD countries. Med Care Res Rev 2009, 66(1):3-22.
7. Musiał-Wysocka A, Kot M, Majka MJCt: The pros and cons of mesenchymal stem cell-based therapies. 2019, 28(7):801-812.
8. Hu C, Zhao L, Zhang L, Bao Q, Li LJSCR, Therapy: Mesenchymal stem cell-based cell-free strategies: safe and effective treatments for liver injury. 2020, 11(1):1-12.
9. Khanam A, Kottilil SJFiM: Acute-on-chronic liver failure: pathophysiological mechanisms and management. 2021, 8:752875.
10. Alfaifi M, Eom YW, Newsome PN, Baik SKJJoh: Mesenchymal stromal cell therapy for liver diseases. 2018, 68(6):1272-1285.
11. Parekkadan B, van Poll D, Megeed Z, Kobayashi N, Tilles AW, Berthiaume F, Yarmush MLJB, communications br: Immunomodulation of activated hepatic stellate cells by mesenchymal stem cells. 2007, 363(2):247-252.
12. Haga S, Terui K, Zhang HQ, Enosawa S, Ogawa W, Inoue H, Okuyama T, Takeda K, Akira S, Ogino TJTJoci: Stat3 protects against Fas-induced liver injury by redox-dependent and-independent mechanisms. 2003, 112(7):989-998.
13. Van Poll D, Parekkadan B, Cho CH, Berthiaume F, Nahmias Y, Tilles AW, Yarmush MLJH: Mesenchymal stem cell–derived molecules directly modulate hepatocellular death and regeneration in vitro and in vivo. 2008, 47(5):1634-1643.
14. Driscoll J, Patel TJJog: The mesenchymal stem cell secretome as an acellular regenerative therapy for liver disease. 2019, 54:763-773.