Pathophysiology of Sepsis and Genesis of Septic Shock: The Critical Role of Mesenchymal Stem Cells (MSCs)

Abstract

The treatment of sepsis and septic shock remains a major public health issue due to the associated morbidity and mortality. Despite an improvement in the understanding of the physiological and pathological mechanisms underlying its genesis and a growing number of studies exploring an even higher range of targeted therapies, no significant clinical progress has emerged in the past decade. In this context, mesenchymal stem cells (MSCs) appear more and more as an attractive approach for cell therapy both in experimental and clinical models. Pre-clinical data suggest a cornerstone role of these cells and their secretome in the control of the host immune response. Host-derived factors released from infected cells (i.e., alarmins, HMGB1, ATP, DNA) as well as pathogen-associated molecular patterns (e.g., LPS, peptidoglycans) can activate MSCs located in the parenchyma and around vessels to upregulate the expression of cytokines/chemokines and growth factors that influence, respectively, immune cell recruitment and stem cell mobilization. However, the way in which MSCs exert their beneficial effects in terms of survival and control of inflammation in septic states remains unclear. This review presents the interactions identified between MSCs and mediators of immunity and tissue repair in sepsis. We also propose paradigms related to the plausible roles of MSCs in the process of sepsis and septic shock. Finally, we offer a presentation of experimental and clinical studies and open the way to innovative avenues of research involving MSCs from a prognostic, diagnostic, and therapeutic point of view in sepsis.

Keywords: circulating MSCs; exosomes; immunomodulation; inflammation; innate immunity; mesenchymal stem cells; miRNA; pericytes; perivascular MSCs; sepsis; septic shock.

Figure 1

Diagram representing the continuum between infection by a pathogen and the occurrence of sepsis complicated or not with a state of shock or even a picture of multi-organ failure and their respective definitions in accordance with the recommendations of the task force and from the survival sepsis campaign. MAP: mean arterial pressure; SOFA score: Sepsis-related Organ Failure Assessment Score.

Figure 2

MSC originate essentially from the mesoderm or the ectoderm (neural crest-NC) embryonic tissues. Differentiated MSC notably of the NC are known to contribute to the peripheral nervous system (and the myelin-forming Schwann cells). They also contribute to important regulatory activities in response to environmental stress and for example to protect the skin from the toxic UV irradiation (role of melanocytes producing melanin pigment to protect keratinocytes). A pool of MSC from either the mesoderm or NC will migrate along blood vessels and will remain associated to endothelial cells later in life. These perivascular MSC form for instance the so-called bone-marrow stem cell niche but they are also the main gatekeepers in all major organs in adults. MSC (at least in culture) are known to differentiate into adipocytes, osteoblasts, or chondrocytes. This differentiation potential has been linked to different pathological settings whereby MSC may be involved either in tissue fibrosis (MSC differentiating into collagen-high producing myofibroblasts), in vessel calcification (osteoblast-like cells) or in fat-high producer adipocyte-like cells involved in atherosclerosis. MSC contribute to the tumor microenvironment while differentiating into cancer-associated fibroblasts (CAF).

Figure 3

Representation of the different physiological roles attributed to MSCs according to their locations within different organs and their interactions with specific tissue-resident cell subpopulations. There are six major physiological roles associated with the MSC: (1) The capacity for neurogenesis represented by the potential for regeneration of myelin and synapses (pruning) and for the genesis of different neuronal and glial cell types; (2) control of apoptosis mediated by soluble mediators; (3) angiogenesis mediated by the secretion of numerous growth factors (e.g., VEGF, Angiopoietin) allowing the construction of nee-vessels and the repair of vessels damaged during tissue attacks; (4) anti-microbial activity by secretion of specialized proteins exerting a direct toxicity on the pathogens such as hepcidin, ß-defensin-2, and LL-37 (cathelicidin hCAP18); (5) the capacity immunomodulation and regulation of the various cellular actors of the immunity by modulating their activation, their proliferation/growth or their differentiation either by direct contact cell- cell either using soluble factors (cytokines, chemokines and non-coding RNAs) exported into the extracellular medium using EVs; and (6) the self-renewal potential of MSCs and their multipotent stem cell character which can lead to the formation of several cell types depending on the conditions of the medium in vivo and in vitro. Ac, astrocyte cells; Exos, exosomes; M1 and M2, macrophages type 1 and 2; MVs, microvesicles; Nc, neuronal cells; NK, natural killer cells; Oc, oligodendrocytes; PRR, pathogen recognition receptor; ROS, reactive oxygen species; TGFß, transforming growth factor ß; TLR, Toll-like receptor; Treg, regulatory T cell.

Figure 4

Illustration of the crosstalks between MSCs and cells of the innate and acquired immune systems during the development and the resolution of septic shock in the host. ① The inflammatory response and activation of the innate immune system at the site of the initial injury allow differentiation and activation of resident immune cells (e.g., macrophages) as well as perivascular MSCs (pMSC), both expressing a myriad of pattern recognition receptors for pathogens (PAMPs) highly conserved motifs (e.g., LPS or nucleic acids for viruses). ② Both cell types will be activated and release factors such as chemokines, cytokines, and growth factors to attract and activate blood-derived innate and adaptative immune cells. Interestingly, pMSC are known to produce the pro-calcitonin (PCT) hormone which is an early marker of the infection (bacterial >> virus) long before the liver acute phase response exemplified by the rise in C reactive protein (CRP) levels. ③ Another biomarker of sepsis, the so-called presepin molecule is the soluble form of the GPI-anchored CD14, coreceptor for LPS and known to be associated with TLR4. The appearance of sCD14 may result from the acute differentiation of circulating monocytes CD14^high/CD16^low into CD14^low/CD16^high (hence releasing CD14) tissue infiltrating cells. Immune cells such as neutrophils and activated MSC can release several bactericidal proteins such as LL37 as well as proteins of the complement system. The latter will contribute to pathogen opsonization, a process in Greek which means “to make the target more appetizing” and that also leads to the formation of the lytic membrane attack complex (MAC, C5b9). MSC but not pathogens will be protected from complement attack on the ground that they express high levels of GPI-anchored regulators (CD55/DAF and CD59/Protectin). ④ pMSC notably derived from the neural crest (associated to vessels and nerves in the bone marrow (BM)) play a critical role in maintaining the hematopoietic stem cells (HSC) in an immuno-privileged niche. For this purpose, MSC of the BM express high levels of the stromal-derived factor 1 (SDF1a/CXCL12) retaining HSC expressing the chemokine receptor CXCR4 (see text). Higher concentrations of CXCL12 produced by pMSC at the site of injury in sepsis will lead to a chemokine gradient in favor of HSC migration in inflamed peripheral. ⑤ pMSC as well as a little-known blood circulating MSC pool (activated in response to PAMPs, DAMPs and immune cytokines (e.g., IFN-gamma produced by T and NK cells)) will be endowed with important immunoregulatory functions (cell-cell contact mechanisms or through the release of exosomes containing regulatory miR and anti-inflammatory cytokines). ⑥ With the ultimate aim to repair the injured tissue, pMSC are well known to release growth factors to drive angiogenesis (VEGF) and/or fibrosis (TGF-β1). Fibrosis is a natural response of tissue healing and associated with the production of extracellular cellular matrix (ECM) proteins (together with matrix metallo-proteases, MMPs) such as collagens. Immune cells and notably polarized M2 anti-inflammatory macrophages are also capable of releasing these growth factors to further contribute to the return of tissue homeostasis.