key: cord-0800642-fjfjpzb0
authors: Sleem, Aleen; Saleh, Fatima
title: Mesenchymal stem cells in the fight against viruses: face to face with the invisible enemy
date: 2020-05-01
journal: Curr Res Transl Med
DOI: 10.1016/j.retram.2020.04.003
sha: ee2d044a752fd2b4410e679ebf35752c4752607d
doc_id: 800642
cord_uid: fjfjpzb0

The relative ease of isolation of mesenchymal stem cells (MSCs) from different tissues coupled with their culture expansion in vitro and their differentiation capacity to mesodermal, endodermal and ectodermal lineages have made these cells attractive for a large number of therapeutic applications. In recent years, there has been remarkable progress in the utilization of MSCs in diverse clinical indications both in animal models and human clinical trials. However, the potential of MSCs to control or treat viral diseases is still in its infancy. In this study, we report quantitative data on the MSC-based clinical trials over the last ten years as they appear on the online database of clinical research studies from US National Institutes of Health. In particular, we provide comprehensive review of either completed or ongoing clinical trials using MSCs for virus-associated diseases focusing on HIV, hepatitis B virus and COVID-19 virus.

haematopoietic and immune system disorders (4); liver injuries (5) ; metabolic disorders (6) ; cancers (7) and much more diseases in the human body that might take advantage of stem cell therapy. Mesenchymal stem or stromal cells (MSCs) in particular are a heterogeneous population of non-hematopoietic stem cells (8) . According to the minimal criteria set by the International Society for Cellular Therapy (ISCT), MSCs are characterized by their adherence to plastic; in vitro differentiation into osteoblasts, adipocytes and chondroblasts; expression of cell surface markers of CD105, CD73, CD44 and CD90 and lack of expression of CD45, CD34, CD11b, CD14, CD79a and HLA-DR (9) . Their multipotential differentiation ability combined with their relative ease of isolation and expansion in vitro have captured the attention of scientists worldwide as an appealing candidate for a wide range of therapeutic applications (10) . Despite initially harvested from the bone marrow , MSCs can now be derived from multiple sources such as adipose tissue, placenta, umbilical cord, dental pulp, skin and others (11) . Given all of the above, the therapeutic use of MSCs for many diseases has been substantially explored which is obvious through the increasing numbers of preclinical and clinical trials of MSC-based products that has risen exponentially over the last 10 years.

During the past decade, research in the field of stem cells has expanded significantly and many trials have been carried out to exploit the ability of MSCs to treat diseases including musculoskeletal, cardiovascular, neurodegenerative and metabolic diseases (12) . However, comparatively, there is less work done in exploring their therapeutic potential in infectious diseases. Even less is known regarding the utility of MSC for the treatment of viral infections.

The emergence of new viruses such as the novel coronavirus disease (COVID-19) virus pose serious threats to public health (13) . Due to the current absence of drugs or vaccines to treat infected patients with COVID-19; scientist are interested in moving from conventional to safe and J o u r n a l P r e -p r o o f effective MSC-based therapies owing to their immunomodulatory and tissue-repair properties (14) . This review will address the development of MSC clinical trials over the last 10 years with in-depth exploration of MSC-based therapies in viral diseases such as HIV, hepatitis and COVID-19.

Data were extracted from ClinicalTrials.gov (NIH, Bethesda, Maryland, USA) using the term "mesenchymal" for trials registered between 1 st of January 2010 and 4 th of March 2020 yielding 923 trials of MSC-based interventions for investigation of their therapeutic potential. The highest activity is found in east Asia (32.6%) mainly China; followed by North America (19.2% with 18.4% in the United States) and Europe coming in third place with 18.1% as shown in Figure 1C .

Currently, China conducts almost 22.5% of all MSC-based trials registered. That is not surprising as the Chinese government has invested a substantial amount of money which is around 3 billion yuan (460 million dollars) to support stem cell and translational research in its twelfth Five-year plan (2011) (2012) (2013) (2014) (2015) . Moreover, China's latest thirteen's Five-year plan for biotechnology that was released in 2016 sets stem cells as one of the key research tasks to be supported.

The total number of registered trials increased linearly from 2010 to 2012, and almost tripled during this period ( Figure 1A ). However, there was a dramatic drop in 2013 followed by slow increase to reach 110 trials in 2015 after which they appear to have plateaued between 2016 and 2018, then the number of new trials seems to pick up in 2019.

The clinical trials were then divided into 8 groups by disease classification and the remainder was designated as others. Based on disease categories, nervous system diseases is the largest group which accounts for 18.1% of all trials. The second most common condition for MSC trials is 

Since HIV was discovered in 1983, researchers worldwide are still haunting an effective treatment for HIV infections (15, 16) . HIV pathogenesis is characterized by selective and progressive loss of CD4 T cells, leading to immunodeficiency in HIV-infected patients (17) . Highly active antiretroviral therapy, referred to as HAART, is very effective in suppressing plasma HIV viral load leading to significant immune restoration and subsequently reduction in morbidity and mortality in chronic HIV-infected patients (18, 19) . However, there is a group of patients known as nonimmune responders (NIRs) who fail to reverse the immunodeficiency despite the full viral suppression making them susceptible to opportunistic infections and thus lower life expectancies as compared to those of immune responders (20) . Therefore, treating HIV-infected HAARTtreated NIRs patients has become a daunting challenge and alternative treatment options are required. In the last decade, stem cell-based therapy provided a glimmer of hope for patients living with HIV. In fact, it was the hematopoietic stem cells (HSCs) that took center stage after the so called 'Berlin patient' was functionally cured from HIV after HSC transplantation with donor cells not expressing the C-C chemokine receptor type 5 (CCR5) which is essential for the HIV entry process (21) . Nearly a decade after the first case of sustained HIV remission in the 'Berlin patient' was announced, Gupta and collaborators reported the second case named 'London patient' who J o u r n a l P r e -p r o o f similarly underwent HSC transplantation with cells lacking CCR5 (22) . However, using allogeneic HSCs in HIV-infected patients is not without its limitations. Strong immunogenicity and occurrence of graft-versus-host disease (GvHD) remain at the forefront of concern when using this allogenic HSC transplantation (23) . Unlike HSCs, hypoimmunogenicity and unique immunosuppressive properties of MSCs have made them attractive candidates for treatment of HIV-infected individuals (24) . Table 1 ).

Although HAART has been very successful in suppressing HIV replication and improving clinical outcomes, it cannot eliminate latent HIV reservoirs and thus fails to cure HIV infection (28).

Therefore, there is an increasing need to develop novel strategies to reactivate latent HIV reservoirs and subsequently enhance their clearance. An in vitro study using latent HIV-infected cell lines reported a novel role for MSCs and MSC-secretome in HIV-1 latency-reactivation through PI3K

and NFκB signaling pathways (29). However, further research is needed to understand the efficacy of MSCs in reactivation of HIV-1 within reservoir microenvironments in vivo.

260 million humans which is more than 3% of the word population and causing more than 880,000 deaths annually due to liver failure or hepatocellular carcinoma (30). HBV-related acute-onchronic liver failure (HBV-ACLF) is observed in populations with chronic HBV infections and associated with high mortality rates due to limited treatment options (31). Current therapies available are nucleos(t)ide analogues that help in reducing cirrhosis and liver-related mortality by suppressing HBV replication, but cannot eliminate the virus (32). Interferon-α treatment can clear HBV in a low number of patients but its use is limited by severe side effects (33). Besides, Artificial Liver Support System (ALSS) therapy has been developed and widely employed for the treatment of patients with HBV-ACLF; however, it is mainly used as a bridge to liver transplantation which is the only highly efficient therapy for HBV-ACLF patients poorlyresponding to standard medical treatment (34). Nevertheless, Liver transplantation is limited because of rapid disease progression and organ scarcity (34,35).

In the era of regenerative medicine, MSCs have emerged as a novel approach for HBV-ACLF treatment due to their ability to home to damaged tissues, hypoimmunogenicity that allows J o u r n a l P r e -p r o o f allogenic transplantation, anti-inflammatory effects and their differentiation capacity into functional hepatocyte-like cells (36, 37) . An study by Peng and colleagues investigated the therapeutic effects of single transfusion of culture expanded autologous Bone marrow (BM)-MSCs in HBV-associated liver failure patients (38) . BM-MSC transplantation was proven safe for those patients with short term efficacy as measured by improvement of albumin, total bilirubin, prothrombin time and Model for End-Stage Liver Disease (MELD) scores compared to the control group (38) . However, the MSC therapy could not markedly improve the clinical laboratory measurements in a long-term follow-up, which could be explained by the slow proliferation of autologous MSCs derived from hepatitis B patients thus delaying timely intervention (38) .

Regarding clinical application of MSCs in HBV-infected patients, there are actually four trials registered at clinicaltrials.gov in the last decade, as shown in Table 1 Despite all the evidence of the MSCs therapeutic abilities in HBV infection suppression, these results are non-conclusive and thus further studies are required specifically to understand the outcomes of the long-term use of MSCs to treat HBV-ACLF and all the mechanisms involved in liver regeneration.

Coronaviruses are members of large viral family causing mild respiratory diseases to severe fatal Leng and colleagues also reported a sharp decline in the major inflammatory marker C-reactive protein as well as pro-inflammatory cytokine TNF-α and a remarkable increase in the antiinflammatory IL-10 in the MSC treated patinets (46) . Thus, the intravenous infusion of MSCs was found to be safe and successful in reversing the virus-induced cytokine storm and enhancing endogenous lung repair by improving the local pulmonary microenvironment (46) . Herein, this pilot study has yielded encouraging data paving the way for more trials on MSCs as a therapeutic approach to patients with COVID-19. (51) . The use of MSC-Exosomes as an alternative to parent MSCs will offer considerable advantages. One advantage is their ability to migrate efficiently to the target site because of their nanosized dimensions without getting physically trapped in microvasculature (52) . Moreover, with MSC exosomes, a higher 'dose' is quite guaranteed to the injured target tissue unlike their counterpart cells whose dose quickly decreases after infusion (53).

Among all types of stem cells, MSCs remain the most commonly used in cell therapy as they are free from ethical concerns with low risk of teratoma formation. Moreover, their immunomodulatory, anti-inflammatory, regenerative capacity as well as homing abilities to damaged tissues have made MSCs a very popular candidate for preclinical and human clinical trials as shown in this review for patients with viral diseases. However, the limitations of these MSC-based therapies should never be underestimated. First, the heterogeneity of MSCs is a serious concern which might explain discrepancies in research results. Also, recent literature has shown increasing evidence that MSCs may not be immunologically silent as assumed previously.

Therefore, there might be need for more research studies to determine ways to isolate the "immune privileged" subpopulations from the heterogeneous pool of MSCs for clinical applications.

Another approach to avoid these limitations is the use of cell-free therapeutic strategies such as MSC-exosomes that will provide considerable benefits over their parent cells especially that the efficacy of MSC therapy appears to derive from the paracrine activity. 

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