Fate and long-lasting therapeutic effects of mesenchymal stromal/stem-like cells: mechanistic insights

Abstract

A large body of evidence suggests that mesenchymal stromal cells (MSCs) are able to respond rapidly to the cytokine milieu following systemic infusion. This encounter has the potential to dictate their therapeutic efficacy (also referred to as licensing). MSCs are able to rapidly react to cellular damage by migrating to the inflamed tissue and ultimately modifying the inflammatory microenvironment. However, the limited use of MSCs in clinical practice can be attributed to a lack of understanding of the fate of MSCs in patients after administration and long term MSC-derived therapeutic activity. While the known physiological effectors of viable MSCs make a relative contribution, an innate property of MSCs as a therapeutic agent is their caspase-dependent cell death. These mechanisms may be involving the functional reprogramming of myeloid phagocytes via efferocytosis, the process by which apoptotic bodies (ABs) are identified for engulfment by both specialized and non-specialized phagocytic cells. Recent studies have provided evidence that the uptake of ABs with a distinct genetic component can induce changes in gene expression through the process of epigenetic remodeling. This phenomenon, known as 'trained immunity', has a significant impact on immunometabolism processes. It is hypothesized that the diversity of recipient cells within the inflammatory stroma adjacent to MSCs may potentially serve as a biomarker for predicting the clinical outcome of MSC treatment, while also contributing to the variable outcomes observed with MSC-based therapies. Therefore, the long-term reconstructive process of MSCs may potentially be mediated by MSC apoptosis and subsequent phagocyte-mediated efferocytosis.

Keywords: Antimicrobial peptide; Apoptosis; Apoptotic bodies; Autophagy; Efferocytosis; Immunoregulation; Long-term effectiveness; Mesenchymal stem cells.

Fig. 1

Linking MSCs apoptosis to immunosuppression mechanisms. The combination of cues to which MSCs are subjected within the tissue stroma, and the resulting intracellular signaling cascade determine the particular immunomodulatory repertoire responsible for orchestrating the MSC-derived therapeutic activity [158]. The immunotherapeutic effect of MSCs is thought to occur in two interrelated phases. However, the fate of MSCs is only partially understood. Experimental data suggest that a hot inflammation (term for a stroma with high levels of inflammatory mediators/inducers such as IFN-γ (phase 1)) [–161] may favor the protection of MSCs from cell-cytotoxicity by distinct mechanisms. While in cold inflammation (term for a stroma with intermediate levels of inflammatory mediators/inducers (phase 2)), the MSCs would behave in a different way. This may have relevant implications for the clinical application of MSCs. Importantly, the presence of different subpopulations of living MSCs, deceased MSCs, late apoptotic MSCs, early apoptotic MSCs, and autophagic cell death should be considered simultaneously [117, 162]. In the early phase, infused MSCs migrate to the focus of inflammation and injury to promote tissue repair and regeneration through paracrine effects, in the next phase apoptotic MSCs effectively regulate various aspects of the recipient cells. The short lifespan of MSCs gradually affected the transplanted cells [163, 164], with MSCs undergoing apoptosis through various mechanisms (described in detail throughout the document). Subsequently, MSC-derived apoptotic bodies are cleared by cells of the myeloid lineage (mainly neutrophils, MQs, and circulating monocytes) [117, 123]. Based on the “dying stem cell hypothesis,” efferocytosis of apoptotic MSCs induces phenotypic and functional changes in phagocytes, which then modulates both innate and adaptive immune responses [123, 164]

Fig. 2

Intercellular communication and potential outcomes between NK cells and MSCs. During the stage phase, MSCs upregulate the cytotoxic capabilities of NK cells. NK-MSC interactions lead to the secretion of IFN-γ by NK cells. Activated MSCs with IFN-γ (MSC1) increase their levels of MHC class I. Boosting MHC class I presentation may provide MSCs with protection against the destruction caused by NK cells [230, 231]. This is accomplished by shifting the balance towards the inhibition of NK cell activity, which results in the transmission of inhibitory signals and the hindrance of the cytotoxic capabilities of NK cells [232]. Nevertheless, there is evidence indicating that MSCs could be regarded as targets sensitive to lysis by activated NK cells [128, 218, 233]. On the contrary, during the resolution phase of inflammation, MSCs in a bioactive mediators-dependent manner induce an inhibitory effect on NK cell proliferation, cytokine secretion, expression of surface-activating receptors, and coreceptors, as well as induce senescence of inflammatory NK cells with a less responsive phenotype [55, 208]. IDO, PGE2, TGF-β, IL-10, and sHLA-G5 are key regulators of the mentioned effects. Furthermore, scientific evidence has demonstrated that MSCs exhibit the capacity to directly hinder the cytotoxic capability of NK cells through the downregulation of perforin and STAT3 [218, 234]. Overall, MSCs have the capability to enhance the cytotoxic activity of NK cells during the initial stages. Subsequently, they have the potential to promote a regulatory phenotype or trigger senescence in activated NK cells [208]. Importantly, it has also been postulated that MSCs exhibit inherent heterogeneity, which may influence the MSC-NK cell interaction [235]. Additionally, MSCs demonstrate varied crosstalk patterns with different NK cell populations [236]