Leptin-Receptor-Expressing Mesenchymal Stromal Cells Represent the Main Source of Bone Formed by Adult Bone Marrow

Zhou, Bo; Yue, Rui; Murphy, Malea M.; Peyer, James G.; Morrison, Sean J.

doi:10.1016/j.stem.2014.06.008

Cited by 1,126 publications

(1,505 citation statements)

References 52 publications

Supporting

Mentioning

1,377

Contrasting

Unclassified

Order By: Relevance

“…These fibroblast-like reticular cells have been generically defined in mice by expression of common markers (leptin receptor and CD140a), and the secretion of large amounts, at least by a substantial fraction of this population, of regulatory factors such as interleukin-7 (IL-7), stem cell factor, and CXCL12. 31,[47][48][49][50] For this feature, they were first visualized in the CXCL12-GFP knock-in mouse model and termed CXCL12-abundant reticular (CAR) cells. 51 Multiple studies have now shown that CAR cells are fundamental players in the regulation of specific and very distinct stages of hematopoiesis.…”

mentioning

confidence: 99%

Quantification and three-dimensional microanatomical organization of the bone marrow

Nombela‐Arrieta

Manz

2017

Blood Advances

View full text Add to dashboard Cite

Bone marrow (BM) constitutes one of the largest organs in mice and humans, continuously generating, in a highly regulated manner, red blood cells, platelets, and white blood cells that together form the majority of cells of the body. In this review, we provide a quantitative overview of BM cellular composition, we summarize emerging knowledge on its structural organization and cellular niches, and we argue for the need of multidimensional approaches such as recently developed imaging techniques to uncover the complex spatial logic that underlies BM function in health and disease.Since Neumann and Bizzozero independently proposed in 1868 that the origin of blood cells was to be found in soft tissues contained inside bone cavities, the bone marrow (BM) has continued to fascinate scientists and clinicians alike. 1,2 Yet more than a century later, our understanding of how the hematopoietic, immune, and bone-forming tasks of the BM are tightly controlled and integrated in the context of one common anatomical space is still incomplete. Methodological approaches and advances to study BM tissuesEarly studies on BM cellular composition and microarchitecture date back to the 19th century when the first biopsies of marrow content were performed in living individuals. 3 Microscopic observation of BM smears and examination of histological sections became the standard technique, which is still used to this day to study, diagnose, and classify hematologic disorders. The realization in the post-World War II era that transplantation of BM cells from healthy individuals could rescue the lethal effects of high-dose irradiation on hematopoiesis galvanized scientific interest in BM and lead to the development of methods to detect and measure hematopoietic stem and progenitor cell (HSPC) activity, absolute cellularity, lineage-specific half-lives, and kinetics of cell production in the BM of humans and in laboratory animals. 4,5 Gradual improvements in light and electron microscopy further refined the understanding of the quantitative composition and ultrastructural features of BM tissues. 6 The biggest leap in the fields of immunology and hematology came with the advent of recombinant antibody technology and flow cytometry in the 1960s. These breakthroughs permitted the identification, quantification, and isolation of diverse populations from highly heterogeneous cell suspensions through detection of phenotypic traits. 5 Indeed, to this day, flow cytometry remains the technological mainstay for the study and dissection of the hematopoietic system.Immunolabeling methods were further adopted in modern fluorescence-based microscopy to discriminate cellular phenotypes in tissue sections and study cellular organization in the BM. In recent years, confocal microscopy has become the most popular modality to define spatial relationships and study developmental-stage specific localization patterns, with a keen interest of many groups in the dissection of HSPC niches. 7 In addition, intravital multiphoton microscopy is employed to obtain dyna...

show abstract

mentioning

confidence: 99%

Quantification and three-dimensional microanatomical organization of the bone marrow

Nombela‐Arrieta

Manz

2017

Blood Advances

View full text Add to dashboard Cite

show abstract

“…A previous study showed that LepR + cells in bone marrow are the major subset of stem/progenitor cells contributing to bone formation and the maintenance of the haematopoietic cell niche in adults (Zhou et al., 2014). We investigated a large proportion of LepR + cells displaying a senescence phenotype in aging mice, and TMP significantly decreased p16 + ‐expressing LepR + cells and instead increased BrdU + ‐labelled LepR + cells (Figure 2a–c).…”

Section: Resultsmentioning

confidence: 99%

“…It is reported that LepR + MSPCs is essential in maintaining the HSC niche (Zhou et al., 2014). To gain more insight into the regulatory effect of TMP on the bone marrow microenvironment and LepR + MSPCs in aging mice, we sorted LepR + MSPCs from 4‐ and 20‐month‐old mice treated with or without TMP and analysed the expression of genes that regulate HSC maintenance and attraction (Cxcl12, c‐kit ligand, angiopoietin‐1, interleukin‐7 and vascular cell adhesion molecule‐1).…”

Section: Resultsmentioning

confidence: 99%

“…Zhou et al. (2014) first demonstrated that LepR + cells in bone marrow were a major source of CFU‐F‐forming MSPCs in adults and formed bone, cartilage, and adipocytes in culture and upon transplantation in vivo. Considering these findings, we sorted LepR + MSPCs from aging mice using flow cytometry and observed that LepR + MSPCs also displayed a senescent phenotype with decreased BrdU labelling, which confirmed the increased cellular senescence of LepR + MSPCs in aging bone marrow.…”

Section: Discussionmentioning

confidence: 99%

“…Likewise, MSC senescence during aging markedly impairs the HSC niche (Iyer, Brooks, Gumbleton, & Kerr, 2015), decreases osteoblast numbers and disrupts epithelial–mesenchymal transition (Zhou et al., 2008). LepR + cells in bone marrow were a major source of CFU‐F‐forming MSPCs in adult and formed bone, cartilage and adipocytes in culture and upon transplantation (Zhou, Yue, Murphy, Peyer, & Morrison, 2014). Additionally, LepR + cells are essential for maintaining the HSC niche through secreting Scf (Asada et al., 2017).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Local delivery of tetramethylpyrazine eliminates the senescent phenotype of bone marrow mesenchymal stromal cells and creates an anti‐inflammatory and angiogenic environment in aging mice

et al. 2018

View full text Add to dashboard Cite

SummaryAging drives the accumulation of senescent cells (SnCs) including stem/progenitor cells in bone marrow, which contributes to aging‐related bone degenerative pathologies. Local elimination of SnCs has been shown as potential treatment for degenerative diseases. As LepR+ mesenchymal stem/progenitor cells (MSPCs) in bone marrow are the major population for forming bone/cartilage and maintaining HSCs niche, whether local elimination of senescent LepR+ MSPCs delays aging‐related pathologies and improves local microenvironment need to be well defined. In this study, we performed local delivery of tetramethylpyrazine (TMP) in bone marrow of aging mice, which previously showed to be used for the prevention and treatment of glucocorticoid‐induced osteoporosis (GIOP). We found the increased accumulation of senescent LepR+ MSPCs in bone marrow of aging mice, and TMP significantly inhibited the cell senescent phenotype via modulating Ezh2‐H3k27me3. Most importantly, local delivery of TMP improved bone marrow microenvironment and maintained bone homeostasis in aging mice by increasing metabolic and anti‐inflammatory responses, inducing H‐type vessel formation, and maintaining HSCs niche. These findings provide evidence on the mechanisms, characteristics and functions of local elimination of SnCs in bone marrow, as well as the use of TMP as a potential treatment to ameliorate human age‐related skeletal diseases and to promote healthy lifespan.

show abstract

Cell–cell signaling pathways that regulate mesenchymal stromal cell differentiation

Etheridge

Mason

Saleh

et al. 2016

The Biology and Therapeutic Application of Mesenchymal Cells

View full text Add to dashboard Cite

Leptin-Receptor-Expressing Mesenchymal Stromal Cells Represent the Main Source of Bone Formed by Adult Bone Marrow

Cited by 1,126 publications

References 52 publications

Quantification and three-dimensional microanatomical organization of the bone marrow

Quantification and three-dimensional microanatomical organization of the bone marrow

Local delivery of tetramethylpyrazine eliminates the senescent phenotype of bone marrow mesenchymal stromal cells and creates an anti‐inflammatory and angiogenic environment in aging mice

Cell–cell signaling pathways that regulate mesenchymal stromal cell differentiation

Contact Info

Product

Resources

About