Mesenchymal Stem Cell Modulation of TH17 Cells Justin D Glenn1 and Katharine a Whartenby1,2*

Glenn et al. Int J Stem Cell Res Ther 2016, 3:035 DOI: 10.23937/2469-570X/1410035 International Journal of Volume 3 | Issue 1 Stem Cell Research & Therapy ISSN: 2469-570X Short Review: Open Access Mesenchymal Stem Cell Modulation of TH17 Cells Justin D Glenn1 and Katharine A Whartenby1,2* 1Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America 2Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America *Corresponding author: Katharine A Whartenby, PhD, Departments of Neurology and Oncology, Johns Hopkins School of Medicine, 601 N. Wolfe Street, Baltimore, Maryland, MD 21287, United States of America, Tel: +1-410- 5023290, Fax: +1-443-2874062, E-mail: [email protected] remarkably were able to undergo adipogenesis, chondrogenesis and Abstract osteogenesis under inducible conditions in culture [9]. Furthermore Mesenchymal stem cells (MSCs) are multi-faceted cells capable dermal skin-derived fibroblasts display similar MSC marker surface of tissue regeneration, wound healing, and immunosuppression. antigen phenotypes, can differentiate into bone, cartilage, and fat, Their immunosuppressive actions extend to most innate and and have high proliferation potential [10]. Other reports have since adaptive immune cells, including T 17 cells, which have recently H shown many similarities and very few differences between the two been discovered to be important pathogenic cells in a variety of disease settings, including many autoimmune diseases. As various cell populations [11-13]. Covas and colleagues even revealed that long-standing treatments and therapies in autoimmune disease fibroblasts and MSCs share a global gene expression pattern [14]. Thus may face limitations and result in dangerous side effects, the field there is still controversy concerning whether MSCs and fibroblasts has searched for safer immunosuppressive therapies, and MSC- are the same cell population, are derived from a common or similar based therapy may hold great potential in controlling chronic TH17- progenitor, or represent a diverse continuum of different cells along based inflammatory conditions. a differentiation pathway that retain fundamental phenotypic and Keywords functional characteristics. For the purpose of this review, we will focus on primary literature based on investigation with cells with Mesenchymal stem cells (MSCs), Inflammation, T 17 H MSC nomenclature. MSCs were initially evaluated for their potential to stimulate Short Review regenerative cellular and molecular pathways in degenerative Mesenchymal stem cells disorders of mesenchymal origin [15]. Early studies demonstrated that the presence of MSCs greatly improved bone marrow transplantation Mesenchymal stem cells compose a heterogeneous stem cell and engraftment, and revealed another action of MSCs which population of the mesenchyme that exhibit multiple functions that contributed to decreased graft rejection-immunosuppression [16,17]. make them appealing to different fields of biomedical and clinical The basis of MSC immunosuppression stems from their physiological research and application. Despite heterogeneity, they have some role of maintaining homeostasis of the hematopoietic stem cell distinctive, shared features including phenotypic characteristics such (HSC)niche in the bone marrow, as inflammatory events may cause as the lack of key hematopoietic molecular markers but expression unsuspected HSC activation, differentiation, and depletion of HSC of cluster of differentiation (CD) 90, CD105, CD44, CD73, CD9 reservoirs [1]. In the HSC niche, MSC-derived fibroblasts have been and low levels of CD80 [1-3]. They were initially identified as self- shown to eliminate survival factors important for immune cells and renewing cells with fibroblastic appearance found in various organs to re-calibrate chemokine gradients, which may limit the presence of and tissues, especially in the bone marrow, where they are thought T cells, when studied in fibroblast dysfunction in the autoimmune to function physiologically as regulators of hematopoietic stem cell disease rheumatoid arthritis [18]. MSCs also migrate from their proliferation and differentiation [4-6]. These cells produce numerous normal anatomical sites to areas of inflammation to suppress growth factors and promote wound healing and angiogenesis [1,7]. In activated T cell proliferation and cytokine production [19,20]. the presence of different molecular milieus, MSCs may differentiate In line with the ultimate MSC physiological goal of maintaining into adipocytes, chondrocytes and osteoblasts. homeostasis, suppression of inflammation permits the proliferation of tissue-resident stromal and stem cells of parenchymal tissue, In the 1970s, Friedenstein and colleagues described the ability of production of extracellular matrix molecules for extracellular tissue splenic fibroblasts to support hematopoietic microenvironments in reconstruction, and wound healing. transplantation experiments [8], suggesting some overlap between fibroblasts and MSCs. Fibroblast cells (which express vimentin, TH17 cells collagen prolyl 4-hydroxylase, and fibronectin) derived from + human adult bronchi strongly express the MSC markers CD73, CD4 T cells are principle adaptive immune cells that function CD105 and CD166, lack expression of CD31, CD34, and CD45, and to coordinate and optimize multi-cellular immune responses and are Citation: Glenn JD, Whartenby KA (2016) Mesenchymal Stem Cell Modulation of TH17 Cells. Int J Stem Cell Res Ther 3:035. doi.org/10.23937/2469-570X/1410035 ClinMed Received: April 28, 2016: Accepted: June 22, 2016: Published: June 26, 2016 International Library Copyright: © 2016 Glenn JD, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. DOI: 10.23937/2469-570X/1410035 ISSN: 2469-570X activated as a function of events perceived as dangerous by the body. via IL-35 production [34]. Although these cell groups are usually Antigen-presenting cells (APCs) such as dendritic cells (DCs) express presented as stable, static effector populations, considerable overlap many classes of pattern recognition receptors that bind endogenous, in master transcription factor expression and cytokine production usually intracellular molecules released from cells during stress and has been demonstrated. Effector populations also exhibit plasticity, necrosis and molecules derived from foreign, non-self-agents such in which one effector population may be converted into another; this as viruses, bacteria, and fungi [21]. In response to “dangerous” phenomenon has mostly been attributed to epigenetic modifications molecule-receptor binding and signaling, DCs up-regulate major that modify gene transcription when T cells are transferred into a histocompatibility complex (MHC) molecules for increased peptide different phenotype-skewing milieu [30]. binding and presentation, enhance T cell co-stimulatory molecule T 17 are important mediators of inflammation in many expression, and produce cytokines that, depending on composition H inflammatory diseases, especially chronic autoimmune diseases and concentration, determine the effector function of the cognate such as rheumatoid arthritis, pancreatitis, autoimmune diabetes, CD4+ T cell. However, they may also mount inappropriate responses and multiple sclerosis (MS). Pre-clinical models of many of these against self-tissue, as is the case in autoimmune pathogenesis. autoimmune diseases show that these cells are important in the Historically, CD4+ T cells were considered to adopt one of two effector pathogenesis. Some of their functions that have been identified include phenotypes that were thought to tailor the ensuing immune response the mobilization of cells and induction of cytokine and chemokine to eliminate pathogens based on location in relation the very cells production, in large part from cells of the innate immune system, [22]. T 1 cells are generated in the presence of the pro-proliferative H including neutrophils and monocytes. An additional critical function cytokine interleukin (IL)-2 and the inflammatory cytokine IL-12 and for central nervous system (CNS) pathology is their association with promote immunity to intracellular pathogens such as bacteria or permeabilization of the blood-brain barrier [26]. For example, people viruses, while T 2 cells develop in the presence of IL-4 and promote H with MS have been shown to have a higher frequency of T 17 cells in immunity to extracellular pathogens including protozoa and fungi. H cerebrospinal fluid than matched counterparts without MS [35,36], The molecules that favor the effector phenotype of each antagonize indicating a flow into and/or expansion of these cells within the CNS. the adoption of the other, and this axis was believed to be exclusive As a further indication of potential pathology the frequency of these until the discovery of CD4+ T cells producing the highly inflammatory T 17 cells is also higher during relapses than during remissions. cytokine IL-17A, now known as T 17 cells [23]. T 17 cells are distinct H H H People with other autoimmune diseases such as systemic lupus from the aforementioned T cell populations at the transcriptional level erythematosus (SLE) have also been shown to have similar patterns, by the expression of the transcription

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