How stem cells speak with host immune cells in inflammatory brain diseases

Abstract

Advances in stem cell biology have raised great expectations that diseases and injuries of the central nervous system (CNS) may be ameliorated by the development of non-hematopoietic stem cell medicines. Yet, the application of adult stem cells as CNS therapeutics is challenging and the interpretation of some of the outcomes ambiguous. In fact, the initial idea that stem cell transplants work only via structural cell replacement has been challenged by the observation of consistent cellular signaling between the graft and the host. Cellular signaling is the foundation of coordinated actions and flexible responses, and arises via networks of exchanging and interacting molecules that transmit patterns of information between cells. Sustained stem cell graft-to-host communication leads to remarkable trophic effects on endogenous brain cells and beneficial modulatory actions on innate and adaptive immune responses in vivo, ultimately promoting the healing of the injured CNS. Among a number of adult stem cell types, mesenchymal stem cells (MSCs) and neural stem/precursor cells (NPCs) are being extensively investigated for their ability to signal to the immune system upon transplantation in experimental CNS diseases. Here, we focus on the main cellular signaling pathways that grafted MSCs and NPCs use to establish a therapeutically relevant cross talk with host immune cells, while examining the role of inflammation in regulating some of the bidirectionality of these communications. We propose that the identification of the players involved in stem cell signaling might contribute to the development of innovative, high clinical impact therapeutics for inflammatory CNS diseases.

Strategies to enhance paracrine potency of transplanted mesenchymal stem cells in intractable neonatal disorders

“…In addition, TLR-4 in MSCs plays pivotal roles in eliminating pathogens by augmenting antibacterial effects and reducing host tissue injuries by attenuating the inflammatory response (90,91). Collectively, these studies suggest that key paracrine factors secreted by MSCs from the same source play important roles in mediating the therapeutic effects of MSCs in different preclinical disease models (11,13,48), suggesting that there is a crosstalk and interplay between the host tissue and transplanted MSCs (61,92). Therefore, unlike drug treatments that deliver a single agent at a specific dose, transplanted MSCs act as a "paracrine factors factory" that sense the microenvironment of the injury site and secrete various paracrine factors that exert several reparative functions, including antiapoptotic, anti-inflammatory, antioxidative, antifibrotic, and/or antibacterial effects in response to local microenvironmental cues to enhance the regeneration of damaged tissue (86).…”

“…Recently, in addition to the cytokines and other secreted molecules mentioned above, MSC derived-extracellular vesicles (EVs) or exosomes (28,40,(61)(62)(63) were shown to be key mediators of MSC therapeutic action (62)(63)(64). EVs derived from MSCs show therapeutic effects on various tissue injury in preclinical animal models by modulating immune response (65), ameliorating oxidative stress (66), and decreasing apoptosis (67), which is similar to what is achieved using the originating MSCs themselves.…”

Stem cells and Bronchopulmonary Dysplasia - The five questions: Which cells, when, in which dose, to which patients via which route?

“…We also have to consider that stem cells encourage the growth and even supplement (host) cells [48]. Additionally, the immunomodulation potential of MSCs may depend on the bidirectional communication between the injured host cells and the graft [49]. Together multiple transplantation routes and graft types have been successfully tested in diverse injury models including BPD.…”

Human Parthenogenetic Embryonic Stem Cell-Derived Neural Stem Cells Express HLA-G and Show Unique Resistance to NK Cell-Mediated Killing

“…In addition to the immunomodulatory functions of HLA-G in respect to NK cells, other aspects determine the fate of transplanted stem cells. For example, NSCs secrete paracrine factors including transforming growth factor (TGF)-β1, prostaglandins (PGE2), nitric oxide (NO) and heme oxygenases (HOs) (54). TGF-β1 maintains immune tolerance, T-cell homeostasis and balances the immunogenicity of NSCs (20,55,56).…”

“…TGF-β1 maintains immune tolerance, T-cell homeostasis and balances the immunogenicity of NSCs (20,55,56). In addition, HOs alone or in combination with NO production mediate immunosuppressive effects of NSCs (57,58), and growth factors and neurotrophins influence stem cell-immune cell interactions (54). Also im- mune-independent parameters, such as the ability to cope with oxidative stress, are critical for stem cell survival in vivo (59).…”