NEWS & VIEWS MUSCULOSKELETAL BIOLOGY AND BIOENGINEERING

A new in vivo stem cell model for regenerative rheumatology Dennis McGonagle and Elena A. Jones Refers to Worthley, D. L. et al. Cell 160, 269–284 (2015) | Chan, C. K. et al. Cell 160, 285–298 (2015)

With advances in stem cell techniques for the bioengineering and regeneration of musculoskeletal tissues comes added complexity in our understanding of stem cell biology. How will the recent discovery of a novel stem cell subset, termed osteochondroreticular stem cells, contribute to progression in the field? For five decades we have known that bone marrow contains clonogenic, highly proliferative stromal cells, variously designated mesenchymal stem cells or multipotent stromal cells (MSC being the acronym for both), with some investigators using the term skeletal stem cells (SSCs). These cells have a b­illionfold expansion capacity with trilineage differentiation potential into fat, bone and cartilage cells. However, the issues associated with ex vivo expansion of MSCs, such as cell senescence, economic cost and considerable regulatory issues, have not helped to pro­ gress MSC-based treatments. Furthermore, MSCs also exist in extraosseous locations,

including the synovium, fat and synovial fluid, with the interrelationships between these different MSC populations being poorly understood. By contrast, a single haematopoietic stem cell (HSC) is capable of recapitulating all cells in the haemato­ poietic system (Figure 1). Published in Cell, two recent studies of native mouse MSCs, by Worthley et al.1 and Chan et al.,2 have important translational implications for rheumato­ logists interested in manipulating stem cells for novel joint-regenerating strategies to treat osteoarthritis (OA). Cartilage can regenerate spontaneously after osteotomy or joint distraction. Noting the aforementioned impressive potential of cultured bone marrow MSCs to form bone and cartilage, delineating the in vivo topo­ graphy, phenotype and function of bone marrow and extraosseous MSCs in health

HSC

◀ Erythrocyte

Platelets Extraosseous MSC

Adipocyte

Leukocyte

BM MSC

Osteoblast

Chondrocyte

OCR

Figure 1 | HSCs are rare undifferentiated cells, primarily located in a bone marrow niche, that exhibit multipotency, with daughter progeny readily circulating and matured cells not regaining stem cell characteristics. The MSC pool comprises distinct skeletal stem cells (perisinusoidal derived tripotent MSCs and putative limb-bud-derived bipotent OCR stem cells) and also diverse extraosseous multipotent MSC populations. Additionally, cells with MSC characteristics are abundant and functionally integrated as fully differentiated supportive stromal cells that can readily de-differentiate in vitro. Reflecting this process, MSCs are more likely to migrate locally than systemically via the vasculature. Abbreviations: BM, bone marrow; HSC, haematopoietic stem cell; MSC, multipotent stem cell (or mesenchymal stromal cell); OCR, osteochondroreticular stem cell.

and disease could contribute considerably to the development of stem-cell-based OA therapy, specifically by manipulating endogenous MSCs. Indeed, in vivo human studies indicate numerical and functional aberrations of MSCs in patients with OA,3 but the approach of tracking native in vivo MSCs in genetically engineered mice offers a more powerful tool to deduce the biology of stem cells in joint homeostasis and disease. In this regard, Worthley and colleagues used cell-tracking experiments to convincingly identify a novel stem cell population, characterized by expression of gremlin1, a bone morphogenetic protein (BMP) antag­onist.1 Termed osteochondroreticular (OCR) stem cells, this population does not express nestin, a robust marker of mouse bone marrow MSCs.4 OCR stem cells are topographically distinct from bone-marrow-­ resident perisinusoidal MSCs; OCR stem cells localize to bony meta­p hyses, have higher proliferation rates and lack adipogenic differentiation potential in vitro and in vivo. Tracking experiments also showed a distinct OCR-type stromal cell in the intestine, but not otherwise outside the em­bryonic limb-bud territory. The major clue to the origin of OCR stem cells described by Worthley et al.1 comes from previous studies of embryological development of the mesoderm, including the limb bud and subsequently the bone marrow cavity.5 During embryonic limb morphogenesis, the initial diaphyseal osteogenesis in the primitive limb mesenchyme is followed by vascular invasion of future bone marrow blood vessels with constituent ‘passenger’ perivascular MSCs needed for blood vessel stabilization and support of the ‘HSC niche’.5 Stated simply, as the limbs develop, the first wave of primitive limb-bud cells is followed by a second wave of migrating perivascular and persinusoidal MSCs, the latter ex­hibiting adipogenic differentiation potential. Worthley et al.1 found that OCR stem cells are vital for skeletogenesis, whereas MSCs gradually increase their skeletal contribution in later life; in support of these findings, both cell populations were shown to participate in fracture repair. Furthermore, not surprisingly, OCR daughter chondrocytes were evident in mature cartilage,1 in keeping with the derivation of cartilage from

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NEWS & VIEWS the limb-bud–joint interzone. No experimental data were provided on the activity of OCR stem cells after joint injury that might simulate OA. We interpret the discovery of OCR stem cells as evidence supporting the persistence of limb-bud-derived MSCs in the adult mouse. Subchondral bone abnormalities are important in OA and, given that OCR stem cells are abundant at the metaphysis, the role of OCR stem-cell progeny in OA bone homeostasis, or deficiency of such cells in elderly individuals, merits further study. This issue requires a number of important considerations, including whether cartilage integrity in adult humans is a legacy of OCR stem cell activity or whether adult joint-resident MSCs take on a homeostatic function, as cartilage (unlike bone) does not have perivascular MSCs. Therefore, OCR cells might have a limited role in physiological articular cartilage repair mechanisms in elderly humans. Publishing back-to-back with Worthley et al.,1 Chan et al.2 tested the hypothesis that the MSC system is hierarchical—with a bonemarrow-resident stem cell and less-potent progeny progressively losing multi­potency and with marrow stem cell or daughter progeny contributing to a peripheral tissue stem-cell reservoir via the systemic circulation—similar to the HSC paradigm. This idea requires a considerable leap of faith as there is little evidence that the skeletal system needs a similar high output rate and thus the same need for tight step-wise control of differentiation. Using genetic tracking experiments with a multi­fluorescent transgenic reporter mouse (rainbow mouse), and experi­ments involving the implantation of different progenitor populations under the renal capsule, the authors showed the existence of primitive, self-renewing MSCs that differentiate into distinct subpopulations of committed progenitor cells, a process re­miniscent of HSC lineage development.2 Chan et al.2 noted that only some of the MSC subpopulations they defined were nestin-positive and there was no evidence that the OCR-like population was among these cells. Of interest, the authors proposed that some progeny of bone marrow MSCs express the leptin receptor and could, therefore, transfer systemic endocrine regulation to both the skeletal and haematopoietic systems, an idea supported by other studies of MSCs.6 Chan et al. 2 also showed that micro­ environmental cues, including BMPs (for

bone) and vascular endothelial growth factors (for ectopic cartilage), activated MSC genetic programmes in extraosseous tissues with bone and cartilage differentiation. This paradigm was first shown with BMPinduced bone formation in ectopic extraskeletal sites by Urist et al.7 Detecting inducible stem cells outside the bone marrow, and following the HSC progeny-cell circulation concept, Chan et al.2 searched for circulating MSCs that might account for their presence in extraskeletal sites:2 no such evidence was found in parabiotic mice (which have shared vascular systems). Furthermore, and unlike the bone marrow experiments, a hierarchical phenotypically discernible MSC population was not detected in extraskeletal tissues. Whether this absence is due to growth factor induction of MSC activity at the ectopic site, or a direct action of BMP on more-mature mesenchymal lineage cells in these tissues, or both, needs to be further clarified, but might have only theoretical value in terms of manipulating MSCs for OA treatment. The in vivo tracking experiments performed by Chan et al.2 did not define an ‘overarching’, robust and unchanging MSC phenotype between bone and other sites—an ongoing problem bedeviling the whole MSC field. It is conceivable that the hier­archical HSC paradigm cannot be imposed on the mesenchyme, for which another paradigm exists (Figure 1). Of particular note, adipocytes and chondrocytes readily form MSC cultures in vitro.8,9 Also, highly-enriched native bone marrow MSC fractions express molecules that are charac­teristic of mature bone marrow stromal cells.4 The adherent nature of MSCs, characterized by fixed tissue locations with anatomical boundary constraints, limited migration and lack of circulation, coupled with the need to be present at multiple sites of potential injury and possess an ability to quickly adapt to the local microenvironment, seem to be key considerations that set MSCs and HSCs apart. The osseous and extraosseous joint tissues and other mesenchyme-derived tissues might contain cells that are able to adopt the stem cell properties of high proliferation and differentiation in response to tissue injury or physiological needs. We term this feature ‘MSC conscription’ as fully functional tissue-resident stromal cells take another guise to protect the tissues when repair is required (Figure 1). The role of MSCs in synovium, superficial cartilage, fat pad and joint fluid, all of which have direct access to damaged

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cartilage, ‘from the top down’, has not yet been deciphered. The limited cell-tracking experi­ments performed thus far in mice provide evidence of an MSC-like synovial population after cartilage injury.10 The challenge now facing rheumatologists is to synthesize insights from mouse MSC biology into a framework for exploiting spontaneous joint repair, joint biomechanics and joint microenvironments, to usher in a new age of regenerative rheumatology. The Mesenchymal Stem Cell Group, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Beckett Street, Leeds LS9 7TF, UK (D.M., E.A.J.). Correspondence to: D.M. [email protected] Acknowledgements Both authors’ research is funded through WELMEC, a Centre of Excellence in Medical Engineering funded by the Wellcome Trust and the Engineering and Physical Sciences Research Council (EPSRC), under grant number WT 088908/Z/09/Z and the NIHR-funded Leeds Biomedical Research Unit. Competing interests The authors declare no competing interests. 1.

Worthley, D. L. et al. Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential. Cell 160, 269–284 (2015). 2. Chan, C. K. et al. Identification and specification of the mouse skeletal stem cell. Cell 160, 285–298 (2015). 3. Jones, E. & McGonagle, D. Human bone marrow mesenchymal stem cells in vivo. Rheumatology (Oxford) 47, 126–131 (2008). 4. Méndez-Ferrer, S. et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010). 5. Bianco, P. & Robey, P. G. Marrow stromal stem cells. J. Clin. Invest. 105, 1663–1668 (2000). 6. Zhou, B. O., Yue, R., Murphy, M. M., Peyer, J. G. & Morrison, S. J. Leptinreceptorexpressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. Cell Stem Cell 15, 154–168 (2014). 7. Urist, M. R., DeLange, R. J. & Finerman, G. A. Bone cell differentiation and growth factors. Science 220, 680–686 (1983). 8. Barbero, A., Ploegert, S., Heberer, M. & Martin, I. Plasticity of clonal populations of dedifferentiated adult human articular chondrocytes. Arthritis Rheum. 48, 1315–1325 (2003). 9. Park, S. R., Oreffo, R. O. & Triffitt, J. T. Interconversion potential of cloned human marrow adipocytes in vitro. Bone 24, 549–554 (1999). 10. Kurth, T. B. et al. Functional mesenchymal stem cell niches in adult mouse knee joint synovium in vivo. Arthritis Rheum. 63, 1289–1300 (2011). Published online 3 March 2015; doi:10.1038/nrrheum.2015.21

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Musculoskeletal biology and bioengineering. A new in vivo stem cell model for regenerative rheumatology.

With advances in stem cell techniques for the bioengineering and regeneration of musculoskeletal tissues comes added complexity in our understanding o...
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