McGonagle-2017-Native joint-resident mesenchym.pdf

The pathogenesis of osteoarthritis(OA)is complex and heterogeneous,with both disease initiation and progres-sion being dependent on multiple joint structures,includ-ing cartilage,bone,ligaments,meniscus and synovium1,2.Many research articles and reviews have emphasized the role of culture-expanded cellular therapies,scaffolds and drugs in the development of therapies for OA,especially for chondrogenic OA,but there is a paucity of data on the use of native(not culture-expanded)joint-resident stem cells in joint-repair strategies.This Review will focus on chondrogenic OA,in which disease initiation and progression seem to be critically dependent on the articular cartilage.The role of subchondral bone,includ-ing the osteochondral junction,is also important in the pathogenesis of OA and has been discussed extensively elsewhere3;therefore,our comments on this subject will largely focus to the role of native bone marrow-resident stem cells,especially at sites of cartilage denudation in advanced OA,where such topographically localized cells can directly access the joint cavity.The pivotal role of articular cartilage loss in OA4,5 and the recognition that cartilage can be restored,albeit with relatively poor-quality repair tissue,following micro-fracture techniques in patients with isolated cartilage lesions or following autologous chondrocyte implanta-tion for the treatment of full-thickness lesions6,7,pointed to the potential importance of cartilage in the develop-ment of therapies for OA.These early studies6,7 suggested that cartilage repair could occur via the actions of highly proliferative cells in close proximity to the cartilage,and were a key impetus for the subsequent culture expansion cellular protocols(first popularised in the 1990s6)and for the subsequent joint-repair strategies that used combina-tions of culture-expanded cells and adjuncts,including scaffolds and pharmaceutical agents8.Although it might not be possible to extrapolate the potential benefits of cellular therapy from results in isolated cartilage defects in young individuals to defects in patients with advanced OA,there is evidence that isolated cartilage lesions in skeletally mature individuals increase in severity over time911,suggesting that advances in the treatment of early lesions could help to prevent OA in later life.Previously,despite spontaneous articular cartilage regeneration being considered unlikely,seemingly mis-guided reparative responses(in the form of chondro-osteophyte formation)were recognized to occur.In the past few years,the spontaneous repair of full-thickness cartilage defects was noted in humans following joint Leeds Institute of Rheumatic and Musculoskeletal Medicine,University of Leeds,Chapel Allerton Hospital,Chapeltown Road,Leeds LS7 4SA,UKCorrespondence to D.M.d.g.mcgonagleleeds.ac.ukdoi:10.1038/nrrheum.2017.182Published online 9 Nov 2017Chondrogenic OAA type of osteoarthritis(OA)in which early lesions form in the articular cartilage;distinct from OA that starts in other structures,such as OA that begins following meniscus or bone injury.Native joint-resident mesenchymal stem cells for cartilage repair in osteoarthritisDennis McGonagle,Thomas G.Baboolal and Elena JonesAbstract|The role of native(not culture-expanded)joint-resident mesenchymal stem cells(MSCs)in the repair of joint damage in osteoarthritis(OA)is poorly understood.MSCs differ from bone marrow-residing haematopoietic stem cells in that they are present in multiple niches in the joint,including subchondral bone,cartilage,synovial fluid,synovium and adipose tissue.Research in experimental models suggests that the migration of MSCs adjacent to the joint cavity is crucial for chonodrogenesis during embryogenesis,and also shows that synovium-derived MSCs might be the primary drivers of cartilage repair in adulthood.In this Review,the available data is synthesized to produce a proposed model in which joint-resident MSCs with access to superficial cartilage are key cells in adult cartilage repair and represent important targets for manipulation in chondrogenic OA,especially in the context of biomechanical correction of joints in early disease.Growing evidence links the expression of CD271,a nerve growth factor(NGF)receptor by native bone marrow-resident MSCs to a wider role for neurotrophins in OA pathobiology,the implications of which require exploration since anti-NGF therapy might worsen OA.Recognizing that joint-resident MSCs are comparatively abundant invivo and occupy multiple niches will enable the optimization of single-stage therapeutic interventions for OA.REVIEWSNATURE REVIEWS|RHEUMATOLOGY VOLUME 13|DECEMBER 2017|719 2017 Macmillan Publishers Limited,part of Springer Nature.All rights reserved.OsteotomyA technique whereby bone is surgically realigned to change the joint alignment and load distribution.Total joint distractionA surgical technique in which external fixator devices are placed across the joint to restore the joint space;associated with cartilage repair.Epiphyseal cartilage ossification centresAreas of the cartilagenous growth plate at the metaphyseal ends of long bones in which bone formation follows the primary ossification seen in the diaphysis of long bones.offloading,either by re-alignment osteotomy12 or by total joint distraction techniques13,14,with neither procedure directly breaching the joint cavity.These reparative events did not depend on cell expansion protocols but instead harnessed native joint-resident or periarticular cells in a manner reminiscent of early microfracture methodolo-gies,which also harnessed endogenous reparative capabil-ities7.Importantly,these procedures highlighted the fact that the addition of scaffolds or growth factors was not essential for endogenous repair in chondrogenic OA15.As such,in this Review we largely confine our comments to the emerging evidence for a cellular basis for regenerative mechanisms in OA,and focus on cartilage repair.At the cellular level,spontaneous cartilage regenera-tion suggests potentially overlapping roles for stem cells from different niches and also for mature chondrocytes(FIG.1).In this Review,we focus on a subgroup of adult stromal cells that are highly proliferative,clonogenic and capable of multi-lineage differentiation into mesenchy-mal tissues including bone,cartilage and adipose tissue.As such,these cells are referred to as mesenchymal stem cells(MSCs),alternatively known as mesenchymal stro-mal cells or marrow stromal cells(when originating from trabecular bone),all of which bear the MSC acronym.Mesenchymal stem cellsThe high proliferative capacity of cultured MSCs and their chondrogenic capabilities have catapulted them to the forefront of cellular therapy development for OA.A large body of literature has accrued on culture-expanded MSCs,which are being trialled as a therapy for OA16,17,but the combination of expense and limited long-term efficacy still presents a major hurdle to the adoption of this therapy.To make such procedures single-stage,there is interest in using off the shelf allogeneic MSCs.Although allogeneic MSCs might have immuno-modulatory effects,they are also associated with poten-tial problems,including loss of functionality following invitro expansion and culture-induced senescence18.The culturing of manipulated cells will not be discussed further in this Review as artificially aged invitro cellu-lar therapies might not function efficiently in the hostile environment of the osteoarthritic joint19.Understanding of the role of MSCs in OA has been influenced by historical misconceptions about MSCs,which originated from our knowledge of haemato logy.In the haematopoietic stem cell(HSC)model,a single HSC can repopulate the entire haematopoietic system20.Like the HSC,the MSC was also viewed as a rare,highly pro-liferative,clonogenic,multipotent cell that could circu-late systemically to reach remote sites21.In hindsight,the shared origin of HSCs and bone marrow-resident MSCs might have resulted in the idea that stem cell progeny can leave the marrow cavity to home to distant sites.In real-ity,however,apart from being co-housed in the skeleton,both systems are radically different;for example,HSCs are rare,quiescent progenitors that reside in a specific niche,whereas cells with MSC-like characteristics can be readily derived invitro from abundant mature stromal cells,including chondrocytes22 and adipocytes23(FIG.1).This evidence supports the idea that fully differentiated somatic cells such as chondrocytes might contribute to tissue repair without the need for differentiation from MSCs or some intermediate cell,and challenges tradi-tional stem cell concepts.Moreover,joint-resident cells with a fibroblastic morphology and features of MSCs can occupy multiple tissue niches(FIG.1).Unlike the HSC model,it is difficult to comprehend how a single MSC could recapitulate the entire skeletal system,and the derivation of an animal model along the same lines as the HSC model is highly improbable.Bone marrow-resident MSCs.Compared with extra-osseous MSCs,our understanding of the biology of bone marrow-resident MSCs is more advanced in terms of phenotype,topography,function and potential therapeutic applications.The bone marrow compart-ment has an important role in advanced OA and MRI-determined bone marrow oedema is prognostically relevant5.Moreover,the theory behind the original stem cell therapy(using microfracture to treat isolated carti-lage defects that are thought to be associated with the development of OA10,11)was predicated on the idea that bone marrow-resident MSCs percolate through to the cartilage from the bone marrow and act as the cellular building blocks for tissue repair24.At birth,the articular cartilage might be indistinguishable from the epiphyseal growth plate in both humans and mice as a result of the secondary epiphyseal cartilage ossification centres having not yet formed25.However,since the focus of this Review is on MSCs in adult joint repair,the intricate links between articular cartilage and the adjacent cartilage of the epiphyseal plate destined to become subchondral bone will only be briefly touched upon with regards to the mechanism of cartilage growth during development and during the neonatal period.Bone marrow-resident MSCs coexist with HSCs,with both cell types able to exert homeostatic control over each others functions26.This unique micro environment seems to have a profound effect on the physiological demands on MSCs:not only do bone marrow-resident MSCs control host tissue remodelling,homeostasis of adipose tissue in bone and bone repair following fracture,but they also sup-port HSC function,maturation and circulatory egress27.Key Points Although historically considered to be very rare cells,native mesenchymal stem cells(MSCs)are actually relatively abundant invivo Joint-resident MSCs occupy several bone and joint cavity niches including synovium,adipose tissue and synovial fluid Advanced osteoarthritis(OA)is associated with a numerical increase,but functional decline,in MSCs in regions of MRI-determined bone oedema,suggesting direct involvement of MSCs in OA pathology invivo The expression of CD271(also known as low-affinity nerve growth factor receptor)on native bone marrow-resident MSCs might be important in pathological bone changes following anti-nerve growth factor therapy In experimental models,there is strong evidence for the involvement of synovium-derived MSCs in cartilage repair following joint injury Emerging features of joint-resident MSCs suggests the potential for their use in the development of single-stage therapy to treat large cartilage defects in patients with OAREVIEWS720|DECEMBER 2017|VOLUME 13 2017 Macmillan Publishers Limited,part of Springer Nature.All rights reserved.In other words,bone marrow-resident MSCs can be con-sidered more multi-functional than MSCs in tissues in which HSC support is not a physiological requirement,such as other tissues of the joint.Moreover,native bone marrow-resident MSCs are part of the adventitial retic-ular compartment(also known as the stromal marrow supportive cellular compartment),which is a functionally mature and abundant cell population2830.The original isolation and characterization of bone marrow-resident MSCs was based on the ability of rare bone marrow-derived cells to adhere to plastic and pro-liferate invitro to form fibroblastic colonies31.In humans,native bone marrow-resident MSCs are characterized by being negative for the expression of haematopoietic cell and endothelial cell markers(for example,CD45 and CD31)and being positive for several other mark-ers such as CD90 and CD73.The most commonly used maker for native bone marrow-resident MSCs is CD271(also known as TNF receptor superfamily member 16,low-affinity nerve growth factor receptor(LNGFR)or p75 receptor)32.Data from the past few years suggest that bone marrow-resident MSCs have diverse embryonic origins(being both neural crest-derived and mesoderm-derived33)and that the relative proportions of cells from each origin might depend on several factors,including bone type and stage of development(for example,whether the bone is from a neonate,a child or an adult)34,35.In mouse models,Gremlin 1+progenitor cells,dubbed osteo-chondroreticular cells,participate in bone repair35.In our opinion,the osteochondroreticular cell population rep-resents a more primitive population of MSCs than those carried into the limb bud during the development of the bone marrow niche,with the latter type of MSCs imbued with both tissue regenerative and haematopoietic support capabilities36.Although osteochondroreticular cells con-tribute to fracture repair in murine models,the role of this population in cartilage repair in OA remains conjectural35.Bone marrow-resident MSCs are the only type of MSC for which a capacity for self-renewal,in the context of rel-evant host tissue regeneration,has been demonstrated invivo at the single-cell level37,38.A single culture-expanded bone marrow-derived MSC can regenerate a whole ectopic bone organ(termed the bone ossicle),containing not only newly formed bone,but also haematopoiesis-supporting stroma that can later be repopulated by host HSCs37.Even though this bone ossicle assay has limita-tions(such as an inability to recapitulate native mechani-cal demands on the formed bone or to be used for testing Figure 1|Stem cells in the joint.The hypothesis that mesenchymal stem cells(MSCs)need to access the circulatory system to reach their destination was adapted from the haematopoetic stem cell(HSC)model.Both MSCs and HSCs are found in the bone marrow,but MSCs have also been described in multiple other niches within the joint,including the periosteum,synovium,adipose tissue(for example,the infrapatellar fat pad)and synovial fluid,as well as other periarticular tissues.Given the avascular nature and considerable thickness of some types of cartilage,a model in which multiple local populatio