Perivascular Mesenchymal Stem/Stromal Cells, an Immune Privileged Niche for Viruses?

Abstract

Mesenchymal stem cells (MSCs) play a critical role in response to stress such as infection. They initiate the removal of cell debris, exert major immunoregulatory activities, control pathogens, and lead to a remodeling/scarring phase. Thus, host-derived ‘danger’ factors released from damaged/infected cells (called alarmins, e.g., HMGB1, ATP, DNA) as well as pathogen-associated molecular patterns (LPS, single strand RNA) can activate MSCs located in the parenchyma and around vessels to upregulate the expression of growth factors and chemoattractant molecules that influence immune cell recruitment and stem cell mobilization. MSC, in an ultimate contribution to tissue repair, may also directly trans- or de-differentiate into specific cellular phenotypes such as osteoblasts, chondrocytes, lipofibroblasts, myofibroblasts, Schwann cells, and they may somehow recapitulate their neural crest embryonic origin. Failure to terminate such repair processes induces pathological scarring, termed fibrosis, or vascular calcification. Interestingly, many viruses and particularly those associated to chronic infection and inflammation may hijack and polarize MSC’s immune regulatory activities. Several reports argue that MSC may constitute immune privileged sanctuaries for viruses and contributing to long-lasting effects posing infectious challenges, such as viruses rebounding in immunocompromised patients or following regenerative medicine therapies using MSC. We will herein review the capacity of several viruses not only to infect but also to polarize directly or indirectly the functions of MSC (immunoregulation, differentiation potential, and tissue repair) in clinical settings.

Exosome-Mediated Antigen Delivery: Unveiling Novel Strategies in Viral Infection Control and Vaccine Design

“…They are multipotent stem cells capable of differentiation into osteoblasts, chondrocytes, and adipocytes [ 201 ]. They were shown to display major immunoregulatory activities to control adverse inflammation and infection [ 202 , 203 ]. Their prominent contribution to immunomodulation and tissue homeostasis positions them as attractive regenerative cells.…”

Immune privileges as a result of mutual regulation of the immune and stem systems

“…2). At the same time, immunoprivileged territories can be used by infectious pathogens as a shelter from the action of the immune system [65]. Infection of stem cells and their niches leads to the impairment of the stem system functions and is expressed by clinical pathologies in the form of fibroses, hematopoiesis disorders, bone and cartilage disorders, damage of the barrier functions in the brain vessels [65].…”

“…At the same time, immunoprivileged territories can be used by infectious pathogens as a shelter from the action of the immune system [65]. Infection of stem cells and their niches leads to the impairment of the stem system functions and is expressed by clinical pathologies in the form of fibroses, hematopoiesis disorders, bone and cartilage disorders, damage of the barrier functions in the brain vessels [65]. The presence of such a potentially dangerous mechanism as stem cell immune privileges must be evolutionarily counterbalanced by equally significant reasons, lest it be rejected in the process of evolution.…”

“…Thus, MSCs activated by inflammatory signals release chemokines that attract immune cells to the damage area, where stem cells can modulate their further activity [69,70]. The hormone procalcitonin produced by MSCs is one of the best and earliest markers of various groups of infectious diseases [65,78]. Procalcitonin levels are significantly elevated long before C-reactive protein levels increase, which is used in intensive care units.…”

“…The immunoregulatory properties of MSC are used for supportive transplantation therapy, and the regenerative potential of MSC is used in regenerative medicine [48,58,69]. Also immune privileges may be involved in the development of cancer and infectious diseases [34,35,64,65]. Thus, the subject matter of this review touches on a wide range of medical issues, including those not addressed in this review.…”