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Are mesenchymal stem cells in rheumatoid arthritis the good or bad guys?

De Bari C - Arthritis Res. Ther. (2015)

Bottom Line: An important question to address relates to the relationship between MSCs and FLSs.MSCs and FLSs could be the same cell type with functional specialisation or represent different functional stages of the same stromal lineage.It will also examine the immunomodulatory properties of the MSCs and the potential to harness such properties for the treatment of RA.

View Article: PubMed Central - PubMed

Affiliation: Regenerative Medicine Group, Musculoskeletal Research Programme, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK. c.debari@abdn.ac.uk.

ABSTRACT
The advancements in our understanding of the inflammatory and immune mechanisms in rheumatoid arthritis (RA) have fuelled the development of targeted therapies that block cytokine networks and pathogenic immune cells, leading to a considerable improvement in the management of RA patients. Nonetheless, no therapy is curative and clinical remission does not necessarily correspond to non-progression of joint damage. Hence, the biomedical community has redirected scientific efforts and resources towards the investigation of other biological aspects of the disease, including the mechanisms driving tissue remodelling and repair. In this regard, stem cell research has attracted extraordinary attention, with the ultimate goal to develop interventions for the biological repair of damaged tissues in joint disorders, including RA. The recent evidence that mesenchymal stem cells (MSCs) with the ability to differentiate into cartilage are present in joint tissues raises an opportunity for therapeutic interventions via targeting intrinsic repair mechanisms. Under physiological conditions, MSCs in the joint are believed to contribute to the maintenance and repair of joint tissues. In RA, however, the repair function of MSCs appears to be repressed by the inflammatory milieu. In addition to being passive targets, MSCs could interact with the immune system and play an active role in the perpetuation of arthritis and progression of joint damage. Like MSCs, fibroblast-like synoviocytes (FLSs) are part of the stroma of the synovial membrane. During RA, FLSs undergo proliferation and contribute to the formation of the deleterious pannus, which mediates damage to articular cartilage and bone. Both FLSs and MSCs are contained within the mononuclear cell fraction in vitro, from which they can be culture expanded as plastic-adherent fibroblast-like cells. An important question to address relates to the relationship between MSCs and FLSs. MSCs and FLSs could be the same cell type with functional specialisation or represent different functional stages of the same stromal lineage. This review will discuss the roles of MSCs in RA and will address current knowledge of the relative identity between MSCs and FLSs. It will also examine the immunomodulatory properties of the MSCs and the potential to harness such properties for the treatment of RA.

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Schematic representations of mesenchymal stem cells (MSCs) and their niches in synovium identified in mice using a double-nucleoside analogue cell-labelling scheme [29]. (A) Schematic drawing of an uninjured control synovial joint. (B) Details of the dashed box in (A), showing cell populations in the synovium of uninjured joints. Iododeoxyuridine (IdU)-retaining cells (green) were located in both the synovial lining (SL) and the subsynovial tissue (SST). Subsets of IdU-positive cells displayed an MSC phenotype. IdU-negative cells (blue) included haematopoietic lineage cells (HC), endothelial cells (EC), pericytes (PC), and other cell types of unknown phenotype. (C) Schematic drawing of a synovial joint 12 days after articular cartilage injury in mice (arrowhead). (D) Details of the dashed box in (C), showing cell populations in the synovium. Proliferating cells were detected in both the synovial lining and the subsynovial tissue and were either double positive for IdU and chlorodeoxyuridine (CIdU; orange) or single positive for CIdU (red). Subsets of cells positive for IdU and CIdU and cells positive only for IdU (green) expressed chondrocyte lineage markers. The boxed areas in (B) and (D) show cell phenotypes. B, bone; C, cartilage; SC, synovial cavity; SM, synovial membrane. Reproduced from Kurth et al., Arthritis Rheum 2011 [29].
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Fig1: Schematic representations of mesenchymal stem cells (MSCs) and their niches in synovium identified in mice using a double-nucleoside analogue cell-labelling scheme [29]. (A) Schematic drawing of an uninjured control synovial joint. (B) Details of the dashed box in (A), showing cell populations in the synovium of uninjured joints. Iododeoxyuridine (IdU)-retaining cells (green) were located in both the synovial lining (SL) and the subsynovial tissue (SST). Subsets of IdU-positive cells displayed an MSC phenotype. IdU-negative cells (blue) included haematopoietic lineage cells (HC), endothelial cells (EC), pericytes (PC), and other cell types of unknown phenotype. (C) Schematic drawing of a synovial joint 12 days after articular cartilage injury in mice (arrowhead). (D) Details of the dashed box in (C), showing cell populations in the synovium. Proliferating cells were detected in both the synovial lining and the subsynovial tissue and were either double positive for IdU and chlorodeoxyuridine (CIdU; orange) or single positive for CIdU (red). Subsets of cells positive for IdU and CIdU and cells positive only for IdU (green) expressed chondrocyte lineage markers. The boxed areas in (B) and (D) show cell phenotypes. B, bone; C, cartilage; SC, synovial cavity; SM, synovial membrane. Reproduced from Kurth et al., Arthritis Rheum 2011 [29].

Mentions: In synovium, MSCs are located mainly in two niches (Figure 1): the lining niche and the sublining perivascular niche, the latter distinct from pericytes [29]. In these two niches, MSCs could have distinct functions and still be geographically interchangeable, but a temporo-spatial hierarchy between the two MSC niches remains to be investigated. Furthermore, MSCs in synovium are heterogeneous in their phenotype, and this could possibly reflect a coexistence of functionally distinct cell subsets [29]. At present, the developmental origins of MSCs in the adult synovium are not known. They could derive from the embryonic joint interzone but a contribution from blood-borne circulating MSCs into the synovial pool would not be surprising given that MSCs can be found in the circulation [30] and are likely to traffic across, home to and engraft in tissues and organs of the entire body. Origins may differ for MSCs found at distinct niche sites. The ontogeny of MSCs in synovium and their maintenance throughout life via possible contribution from other tissues such as bone marrow is an exciting area of investigation.Figure 1


Are mesenchymal stem cells in rheumatoid arthritis the good or bad guys?

De Bari C - Arthritis Res. Ther. (2015)

Schematic representations of mesenchymal stem cells (MSCs) and their niches in synovium identified in mice using a double-nucleoside analogue cell-labelling scheme [29]. (A) Schematic drawing of an uninjured control synovial joint. (B) Details of the dashed box in (A), showing cell populations in the synovium of uninjured joints. Iododeoxyuridine (IdU)-retaining cells (green) were located in both the synovial lining (SL) and the subsynovial tissue (SST). Subsets of IdU-positive cells displayed an MSC phenotype. IdU-negative cells (blue) included haematopoietic lineage cells (HC), endothelial cells (EC), pericytes (PC), and other cell types of unknown phenotype. (C) Schematic drawing of a synovial joint 12 days after articular cartilage injury in mice (arrowhead). (D) Details of the dashed box in (C), showing cell populations in the synovium. Proliferating cells were detected in both the synovial lining and the subsynovial tissue and were either double positive for IdU and chlorodeoxyuridine (CIdU; orange) or single positive for CIdU (red). Subsets of cells positive for IdU and CIdU and cells positive only for IdU (green) expressed chondrocyte lineage markers. The boxed areas in (B) and (D) show cell phenotypes. B, bone; C, cartilage; SC, synovial cavity; SM, synovial membrane. Reproduced from Kurth et al., Arthritis Rheum 2011 [29].
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4416346&req=5

Fig1: Schematic representations of mesenchymal stem cells (MSCs) and their niches in synovium identified in mice using a double-nucleoside analogue cell-labelling scheme [29]. (A) Schematic drawing of an uninjured control synovial joint. (B) Details of the dashed box in (A), showing cell populations in the synovium of uninjured joints. Iododeoxyuridine (IdU)-retaining cells (green) were located in both the synovial lining (SL) and the subsynovial tissue (SST). Subsets of IdU-positive cells displayed an MSC phenotype. IdU-negative cells (blue) included haematopoietic lineage cells (HC), endothelial cells (EC), pericytes (PC), and other cell types of unknown phenotype. (C) Schematic drawing of a synovial joint 12 days after articular cartilage injury in mice (arrowhead). (D) Details of the dashed box in (C), showing cell populations in the synovium. Proliferating cells were detected in both the synovial lining and the subsynovial tissue and were either double positive for IdU and chlorodeoxyuridine (CIdU; orange) or single positive for CIdU (red). Subsets of cells positive for IdU and CIdU and cells positive only for IdU (green) expressed chondrocyte lineage markers. The boxed areas in (B) and (D) show cell phenotypes. B, bone; C, cartilage; SC, synovial cavity; SM, synovial membrane. Reproduced from Kurth et al., Arthritis Rheum 2011 [29].
Mentions: In synovium, MSCs are located mainly in two niches (Figure 1): the lining niche and the sublining perivascular niche, the latter distinct from pericytes [29]. In these two niches, MSCs could have distinct functions and still be geographically interchangeable, but a temporo-spatial hierarchy between the two MSC niches remains to be investigated. Furthermore, MSCs in synovium are heterogeneous in their phenotype, and this could possibly reflect a coexistence of functionally distinct cell subsets [29]. At present, the developmental origins of MSCs in the adult synovium are not known. They could derive from the embryonic joint interzone but a contribution from blood-borne circulating MSCs into the synovial pool would not be surprising given that MSCs can be found in the circulation [30] and are likely to traffic across, home to and engraft in tissues and organs of the entire body. Origins may differ for MSCs found at distinct niche sites. The ontogeny of MSCs in synovium and their maintenance throughout life via possible contribution from other tissues such as bone marrow is an exciting area of investigation.Figure 1

Bottom Line: An important question to address relates to the relationship between MSCs and FLSs.MSCs and FLSs could be the same cell type with functional specialisation or represent different functional stages of the same stromal lineage.It will also examine the immunomodulatory properties of the MSCs and the potential to harness such properties for the treatment of RA.

View Article: PubMed Central - PubMed

Affiliation: Regenerative Medicine Group, Musculoskeletal Research Programme, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK. c.debari@abdn.ac.uk.

ABSTRACT
The advancements in our understanding of the inflammatory and immune mechanisms in rheumatoid arthritis (RA) have fuelled the development of targeted therapies that block cytokine networks and pathogenic immune cells, leading to a considerable improvement in the management of RA patients. Nonetheless, no therapy is curative and clinical remission does not necessarily correspond to non-progression of joint damage. Hence, the biomedical community has redirected scientific efforts and resources towards the investigation of other biological aspects of the disease, including the mechanisms driving tissue remodelling and repair. In this regard, stem cell research has attracted extraordinary attention, with the ultimate goal to develop interventions for the biological repair of damaged tissues in joint disorders, including RA. The recent evidence that mesenchymal stem cells (MSCs) with the ability to differentiate into cartilage are present in joint tissues raises an opportunity for therapeutic interventions via targeting intrinsic repair mechanisms. Under physiological conditions, MSCs in the joint are believed to contribute to the maintenance and repair of joint tissues. In RA, however, the repair function of MSCs appears to be repressed by the inflammatory milieu. In addition to being passive targets, MSCs could interact with the immune system and play an active role in the perpetuation of arthritis and progression of joint damage. Like MSCs, fibroblast-like synoviocytes (FLSs) are part of the stroma of the synovial membrane. During RA, FLSs undergo proliferation and contribute to the formation of the deleterious pannus, which mediates damage to articular cartilage and bone. Both FLSs and MSCs are contained within the mononuclear cell fraction in vitro, from which they can be culture expanded as plastic-adherent fibroblast-like cells. An important question to address relates to the relationship between MSCs and FLSs. MSCs and FLSs could be the same cell type with functional specialisation or represent different functional stages of the same stromal lineage. This review will discuss the roles of MSCs in RA and will address current knowledge of the relative identity between MSCs and FLSs. It will also examine the immunomodulatory properties of the MSCs and the potential to harness such properties for the treatment of RA.

Show MeSH
Related in: MedlinePlus