Mesenchymal stem cells for the management of rheumatoid arthritis: Immune modulation, repair or both?

Purpose of review Mesenchymal stromal/stem cells (MSCs) have potent anti-inflammatory and immunomodulatory properties, in addition to their ability to form cartilage and bone. The purpose of this review is to highlight recent developments and current knowledge gaps in our understanding of the protective effects of MSCs against inflammatory arthritis, and to discuss their clinical exploitation for the treatment of rheumatoid arthritis (RA). Recent findings The weight of evidence for protective mechanisms of exogenously administered MSCs is on immunomodulatory effects, including inhibition of dendritic cell maturation, polarization of macrophages to an anti-inflammatory phenotype, and activation of regulatory T cells, thereby dampening inflammation and preventing joint damage. Evidence for direct effects on tissue repair is scant. Recent studies have identified MSC subsets in vivo and an important question is whether MSCs in their native tissues have similar immunoregulatory functions. Recent proof-of-concept clinical studies have shown a satisfactory safety profile of allogeneic MSC therapy in RA patients with promising trends for clinical efficacy. Summary Allogeneic MSCs could be effective in RA. Larger, multicentre clinical studies are needed to provide robust evidence, and MSC treatment at early stages of RA should be explored to 'reset' the immune system

Joint morphogenetic cells in the adult mammalian synovium

The stem cells that safeguard synovial joints in adulthood are undefined. Studies on mesenchymal stromal/stem cells (MSCs) have mainly focused on bone marrow. Here we show that lineage tracing of Gdf5-expressing joint interzone cells identifies in adult mouse synovium an MSC population largely negative for the skeletal stem cell markers Nestin-GFP, Leptin receptor and Gremlin1. Following cartilage injury, Gdf5-lineage cells underpin synovial hyperplasia through proliferation, are recruited to a Nestin-GFP high perivascular population, and contribute to cartilage repair. The transcriptional co-factor Yap is upregulated after injury, and its conditional ablation in Gdf5-lineage cells prevents synovial lining hyperplasia and decreases contribution of Gdf5-lineage cells to cartilage repair. Cultured Gdf5-lineage cells exhibit progenitor activity for stable chondrocytes and are able to self-organize three-dimensionally to form a synovial lining-like layer. Finally, human synovial MSCs transduced with Bmp7 display morphogenetic properties by patterning a joint-like organ in vivo. Our findings further the understanding of the skeletal stem/progenitor cells in adult life

Targeting GD2-positive glioblastoma by chimeric antigen receptor empowered mesenchymal progenitors

Tumor targeting by genetically modified mesenchymal stromal/stem cells (MSCs) carrying anti-cancer molecules represents a promising cell-based strategy. We previously showed that the pro-apoptotic agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can be successfully delivered by MSCs to cancer sites. While the interaction between TRAIL and its receptors is clear, more obscure is the way in which MSCs can selectively target tumors and their antigens. Several neuroectoderm-derived neoplasms, including glioblastoma (GBM), sarcomas, and neuroblastoma, express high levels of the tumor-associated antigen GD2. We have already challenged this cell surface disialoganglioside by a chimeric antigen receptor (CAR)-T cell approach against neuroblastoma. With the intent to maximize the therapeutic profile of MSCs delivering TRAIL, we here originally developed a bi-functional strategy where TRAIL is delivered by MSCs that are also gene modified with the truncated form of the anti-GD2 CAR (GD2 tCAR) to mediate an immunoselective recognition of GD2-positive tumors. These bi-functional MSCs expressed high levels of TRAIL and GD2 tCAR associated with a robust anti-tumor activity against GD2-positive GBM cells. Most importantly, the anti-cancer action was reinforced by the enhanced targeting potential of such bi-functional cells. Collectively, our results suggest that a truncated anti-GD2 CAR might be a powerful new tool to redirect MSCs carrying TRAIL against GD2-expressing tumors. This affinity-based dual targeting holds the promise to combine site-specific and prolonged retention of MSCs in GD2-expressing tumors, thereby providing a more effective delivery of TRAIL for still incurable cancers

Strategies for improved targeting of therapeutic cells: implications for tissue repair

Multipotent mesenchymal stem cells (MSCs) have been suggested as a suitable cell source for cell-based treatments for diseases such as osteoarthritis due to their ability to differentiate towards chondrogenic and osteogenic lineages. MSCs can be obtained from a variety of tissue sources, are scalable for mass-production and immuno-privileged enabling their use for allogeneic cell therapy. However, recent pre-clinical studies and clinical trials point to the necessity of increasing engraftment and efficacy of MSCs. This review explores how cell surface modification of the cells can improve homing of MSCs and summarises the use of nanoparticles to enable gene delivery by stem cells as well as facilitate in vivo imaging. The use of advanced biomaterials and how they can be applied to reduce the overall dose of MSCs during therapeutic interventions while achieving optimal targeting efficiency of cells to the diseased sites are addressed. Particular attention is paid to methods that improve engraftment of MSCs to cartilage and research describing combinatorial approaches of particle-based cell therapies for improved regeneration of this tissue is reviewed. The use of such approaches will add to the array of potential regenerative therapeutics for treatment of osteoarthritis

Strategies for improved targeting of therapeutic cells: implications for tissue repair

Multipotent mesenchymal stem cells (MSCs) have been suggested as a suitable cell source for cell-based treatments for diseases such as osteoarthritis due to their ability to differentiate towards chondrogenic and osteogenic lineages. MSCs can be obtained from a variety of tissue sources, are scalable for mass-production and immuno-privileged enabling their use for allogeneic cell therapy. However, recent pre-clinical studies and clinical trials point to the necessity of increasing engraftment and efficacy of MSCs. This review explores how cell surface modification of the cells can improve homing of MSCs and summarises the use of nanoparticles to enable gene delivery by stem cells as well as facilitate in vivo imaging. The use of advanced biomaterials and how they can be applied to reduce the overall dose of MSCs during therapeutic interventions while achieving optimal targeting efficiency of cells to the diseased sites are addressed. Particular attention is paid to methods that improve engraftment of MSCs to cartilage and research describing combinatorial approaches of particle-based cell therapies for improved regeneration of this tissue is reviewed. The use of such approaches will add to the array of potential regenerative therapeutics for treatment of osteoarthritis

Strategies for improved targeting of therapeutic cells: Implications for tissue repair

Multipotent mesenchymal stem cells (MSCs) have been suggested as a suitable cell source for cell-based treatments for diseases such as osteoarthritis due to their ability to differentiate towards chondrogenic and osteogenic lineages. MSCs can be obtained from a variety of tissue sources, are scalable for mass-production and immuno-privileged enabling their use for allogeneic cell therapy. However, recent pre-clinical studies and clinical trials point to the necessity of increasing engraftment and efficacy of MSCs. This review explores how cell surface modification of the cells can improve homing of MSCs and summarises the use of nanoparticles to enable gene delivery by stem cells as well as facilitate in vivo imaging. The use of advanced biomaterials and how they can be applied to reduce the overall dose of MSCs during therapeutic interventions while achieving optimal targeting efficiency of cells to the diseased sites are addressed. Particular attention is paid to methods that improve engraftment of MSCs to cartilage and research describing combinatorial approaches of particle-based cell therapies for improved regeneration of this tissue is reviewed. The use of such approaches will add to the array of potential regenerative therapeutics for treatment of osteoarthritis

POS0069 INCREASED T CELL RESPONSES, METABOLIC ACTIVITY AND FIBROBLAST INVASIVE CAPACITY IN CHILDREN WITH DOWN’S SYNDROME-ASSOCIATED ARTHRITIS COMPARED TO JUVENILE IDIOPATHIC ARTHRITIS

Background:Juvenile idiopathic arthritis (JIA) was thought to be the most common inflammatory arthritis in children (Shih et al., 2019). However an aggressive, erosive arthritis of little-known immunologic mechanism occurs 20 times more frequently in children with Down’s syndrome (Foley et al., 2019).Objectives:This study was undertaken to characterize immune cell responses and synovial fibroblast invasiveness in children with Down’s syndrome-associated arthritis (DA).Methods:Multiparametric flow cytometric analysis was used to examine peripheral blood T cell, B cell and monocyte populations. In addition, T cell cytokine responses and their metabolic profile in children with DA, JIA, Down’s Syndrome (trisomy 21 [T21]), and in healthy controls were assessed. The function of DA primary synovial fibroblasts (FLS) was assessed in response to stimulation with pro-inflammatory mediators alone and in combination (TNF-α, IL-17a, IFN-γ, GM-CSF). The two major energy pathways glycolysis (ECAR) and oxidative phosphorylation (OCR) were quantified by the Seahorse XFe96 Analyser. Migration, adhesion, invasion and cytokine/chemokine secretion were quantified by wound repair scratch assays, Transwell collagen invasion chambers, adhesion binding assays, and ELISAs.Results:T cell frequencies were higher in DA compared to JIA and T21 in contrast to B cell frequencies which were decreased. T cell responses in DA were characterized by increased frequencies of CD4+ and CD8+ TNF- α, IFN- γ and GM-CSF producing T cells. The frequency of T peripheral helper (Tph) cells were elevated in children with DA compared to all other groups. In parallel, an increase in their metabolic profile evident by higher phosphorylation of mTOR pathway components AKT, mTOR and S6. Comparison of DA and JIA FLS demonstrated that DA FLS display a more invasive/migratory capacity and are more metabolically active. Based on the increased cytokine responses in DA T cells, we next examined the effect T cell derived cytokines TNF-α, IL-17A, IFN-γ and GM-CSF alone and in combination on DA FLS function. TNF-α, IL-17a and IFN-γ induced IL-6, RANTES and MCP-1 secretion, with no effect observed for GM-CSF. Furthermore, TNF-α and IL-17A induced DA FLS migration and PBMC adhesion to DA FLS. Finally IL17A and IFN-γ potentiated the effect of TNF-α on IL-6 and MCP-1 secretion compared to stimulations alone.Conclusion:DA is a more common and aggressive form of arthritis compared to JIA. It is characterized by increased T cell responses and a more invasive FLS phenotype compared to that of JIA, with T cell derived cytokine alone and in combination further inducing DA FLS pathogenic mechanisms. These effects mirror the increased erosive disease observed clinically.References:[1]Foley, C. et al. (2019) ‘Increased T cell plasticity with dysregulation of T follicular helper, T peripheral helper and T regulatory cell responses in children with JIA and Down syndrome-associated arthritis’, Arthritis &amp; Rheumatology, pp. 0–1. doi: 10.1002/art.41150.[2]Shih, Y. J. et al. (2019) ‘Enthesitis-related arthritis is the most common category of juvenile idiopathic arthritis in Taiwan and presents persistent active disease’, Pediatric Rheumatology. Pediatric Rheumatology. doi: 10.1186/s12969-019-0363-0.Disclosure of Interests:None declared.</jats:sec