Endogenous Bone Marrow MSCs Are Dynamic, Fate-Restricted Participants in Bone Maintenance and Regeneration

Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Cell stem cell (Impact Factor: 22.27). 03/2012; 10(3):259-72. DOI: 10.1016/j.stem.2012.02.003


Mesenchymal stem cells (MSCs) commonly defined by in vitro functions have entered
clinical application despite little definition of their function in residence.
Here, we report genetic pulse-chase experiments that define osteoblastic cells as
short-lived and nonreplicative, requiring replenishment from bone-marrow-derived,
Mx1(+) stromal cells with "MSC" features. These cells respond to tissue stress
and migrate to sites of injury, supplying new osteoblasts during fracture
healing. Single cell transplantation yielded progeny that both preserve
progenitor function and differentiate into osteoblasts, producing new bone. They
are capable of local and systemic translocation and serial transplantation. While
these cells meet current definitions of MSCs in vitro, they are osteolineage
restricted in vivo in growing and adult animals. Therefore, bone-marrow-derived
MSCs may be a heterogeneous population with the Mx1(+) population, representing a
highly dynamic and stress responsive stem/progenitor cell population of
fate-restricted potential that feeds the high cell replacement demands of the
adult skeleton.

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    • "Osterix (OSX) is a transcription factor that is expressed by precursors that first appear in the perichondrium and invade primary ossification centers in parallel with blood vessels to give rise to mature bone cells (Maes et al., 2010; Nakashima et al., 2002). Until recently, OSX-expressing cells were thought to be committed progenitors that transiently contribute to bone remodeling at least in adult mice (Park et al., 2012). However, perinatal OSX+ cells appear to contain MSCs that demonstrated high CFU-F activity in addition to the ability of trilineage differentiation in vitro (Mizoguchi et al., 2014). "
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    ABSTRACT: Mesenchymal stromal cells (MSCs) are heterogeneous and primitive cells discovered first in the bone marrow (BM). They have putative roles in maintaining tissue homeostasis and are increasingly recognized as components of stem cell niches, which are best defined in the blood. The absence of in vivo MSC markers has limited our ability to track their behavior in vivo and draw comparisons with in vitro observations. Here we review the historical background of BM-MSCs, advances made in their prospective isolation, their developmental origin and contribution to maintaining subsets of hematopoietic cells, and how mesenchymal cells contribute to other stem cell niches. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell Stem Cell 03/2015; 16(3):239-253. DOI:10.1016/j.stem.2015.02.019 · 22.27 Impact Factor
    • "Contributions from the sympathetic nervous system and abnormalities in the myelomaassociated extracellular matrix also can support multiple myeloma progression . Perturbation of the osteoblast can lead directly, and spontaneously , to myelodysplasia or AML [35] [36], demonstrating the critical influence of the bone microenvironment on hematological malignancies. "
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    ABSTRACT: Multiple myeloma is a B-cell malignancy characterized by the unrelenting proliferation of plasma cells. Multiple myeloma causes osteolytic lesions and fractures that do not heal due to decreased osteoblastic and increased osteoclastic activity. However, the exact relationship between osteoblasts and myeloma cells remains elusive. Understanding the interactions between these dynamic bone-forming cells and myeloma cells is crucial to understanding how osteolytic lesions form and persist, and how tumors grow within the bone marrow. This review provides a comprehensive overview of basic and translational research focused on the role of osteoblasts in multiple myeloma progression and their relationship to osteolytic lesions. Importantly, current challenges for in vitro studies exploring direct osteoblastic effects on myeloma cells, and gaps in understanding the role of the osteoblast in myeloma progression are delineated. Finally, successes and challenges in myeloma treatment with osteoanabolic therapy (i.e. any treatment that induces increased osteoblastic number or activity) are enumerated. Our goal is to illuminate novel mechanisms by which osteoblasts may contribute to multiple myeloma disease progression and osteolysis to better direct research efforts. Ultimately, we hope this may provide a roadmap for new approaches to the pathogenesis and treatment of multiple myeloma with a particular focus on the osteoblast. Copyright © 2015. Published by Elsevier Inc.
    Bone 02/2015; 75. DOI:10.1016/j.bone.2015.02.021 · 3.97 Impact Factor
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    • "However, bone anabolic therapeutics may act as an important adjunct for advanced osteoporosis to regenerate lost tissue [3] [4]. Given the limited lifespan of the osteoblast [5], bone anabolism requires the continued replenishment of the exhausted osteoblast from an osteoprogenitor population [6e8]. However, little is known regarding the biochemical cues that mediate replenishment from the stem cell niche. "
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    ABSTRACT: Bone formation requires the recruitment, proliferation and osteogenic differentiation of mesenchymal progenitors. A potent stimulus driving this process is mechanical loading, yet the signalling mechanisms underpinning this are incompletely understood. The objective of this study was to investigate the role of the mechanically-stimulated osteocyte and osteoblast secretome in coordinating progenitor contributions to bone formation. Initially osteocytes (MLO-Y4) and osteoblasts (MC3T3) were mechanically stimulated for 24hrs and secreted factors within the conditioned media were collected and used to evaluate mesenchymal stem cell (MSC) and osteoblast recruitment, proliferation and osteogenesis. Paracrine factors secreted by mechanically stimulated osteocytes significantly enhanced MSC migration, proliferation and osteogenesis and furthermore significantly increased osteoblast migration and proliferation when compared to factors secreted by statically cultured osteocytes. Secondly, paracrine factors secreted by mechanically stimulated osteoblasts significantly enhanced MSC migration but surprisingly, in contrast to the osteocyte secretome, inhibited MSC proliferation when compared to factors secreted by statically cultured osteoblasts. A similar trend was observed in osteoblasts. This study provides new information on mechanically driven signalling mechanisms in bone and highlights a contrasting secretome between cells at different stages in the bone lineage, furthering our understanding of loading-induced bone formation and indirect biophysical regulation of osteoprogenitors. Copyright © 2015. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 02/2015; 459(1). DOI:10.1016/j.bbrc.2015.02.080 · 2.30 Impact Factor
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