Hox11 expressing regional skeletal stem cells are progenitors for osteoblasts, chondrocytes and adipocytes throughout life

Pineault, Kyriel M.; Song, Jane Y.; Kozloff, Kenneth M.; Lucas, Daniel; Wellik, Deneen M.

doi:10.1038/s41467-019-11100-4

Cited by 88 publications

(108 citation statements)

References 37 publications

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“…A Hoxa11eGFP knock-in reporter allele shows that Hox expression initiates broadly at embryonic day (E) ∼9.5 within the developing limb bud mesenchyme but very quickly becomes restricted to the zeugopod region (6,7). While previous work has focused largely on the embryonic role of Hox genes, we observed that expression is continuous in the skeleton and extends beyond development into postnatal and adult stages (7)(8)(9)(10)(11). Importantly, Hox expression remains regionally restricted and maintains the expression pattern that has been established during development (9,12,13).…”

mentioning

confidence: 72%

“…We previously demonstrated that Hox11 expression in the skeleton is exclusively restricted to a population of regional, progenitor-enriched mesenchymal stem/stromal cells (MSCs) (9,11). Using a Hoxa11-CreER T2 lineage-tracing system, we recently established that the Hox11 lineage contributes to the development, growth, and homeostasis of the zeugopod skeleton by giving rise to all of the mesenchymal lineages in the boneosteoblasts, osteocytes, chondrocytes, and bone marrow adipocytes.…”

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confidence: 99%

“…Using a Hoxa11-CreER T2 lineage-tracing system, we recently established that the Hox11 lineage contributes to the development, growth, and homeostasis of the zeugopod skeleton by giving rise to all of the mesenchymal lineages in the boneosteoblasts, osteocytes, chondrocytes, and bone marrow adipocytes. Notably, this Hox11-expressing cell population is also maintained as self-renewing adult stem cells throughout life, demonstrating that Hox-expressing cells are bona fide skeletal stem cells (SSCs), continuously supplying the progenitors for bone maintenance and repair throughout the life of the animal (11).…”

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confidence: 99%

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Hox genes maintain critical roles in the adult skeleton

Song

Pineault

Dones

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Hox genes are indispensable for the proper patterning of the skeletal morphology of the axial and appendicular skeleton during embryonic development. Recently, it has been demonstrated that Hox expression continues from embryonic stages through postnatal and adult stages exclusively in a skeletal stem cell population. However, whether Hox genes continue to function after development has not been rigorously investigated. We generated a Hoxd11 conditional allele and induced genetic deletion at adult stages to show that Hox11 genes play critical roles in skeletal homeostasis of the forelimb zeugopod (radius and ulna). Conditional loss of Hox11 function at adult stages leads to replacement of normal lamellar bone with an abnormal woven bone-like matrix of highly disorganized collagen fibers. Examining the lineage from the Hox-expressing mutant cells demonstrates no loss of stem cell population. Differentiation in the osteoblast lineage initiates with Runx2 expression, which is observed similarly in mutants and controls. With loss of Hox11 function, however, osteoblasts fail to mature, with no progression to osteopontin or osteocalcin expression. Osteocyte-like cells become embedded within the abnormal bony matrix, but they completely lack dendrites, as well as the characteristic lacuno-canalicular network, and do not express SOST. Together, our studies show that Hox11 genes continuously function in the adult skeleton in a region-specific manner by regulating differentiation of Hox-expressing skeletal stem cells into the osteolineage.

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confidence: 72%

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confidence: 99%

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confidence: 99%

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Hox genes maintain critical roles in the adult skeleton

Song

Pineault

Dones

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Lineage tracing data shows that in the postnatal period certain Hox-positive MSC (for example, expressing Hoxa11) do not arise from Hox-negative ones, but originate from pre-existed mesoangioblasts (Pineault et al, 2019). Thus, the expression of Hox genes in tissue-resident MSC does not seem to "turn on" in the postnatal period but rather remains unrepressed in some cells after birth.…”

Section: Postnatal Expression Of Hox In Stromal Cells: Memorizing Locmentioning

confidence: 99%

Hox-Positive Adult Mesenchymal Stromal Cells: Beyond Positional Identity

Kulebyakina

Макаревич

2020

Front. Cell Dev. Biol.

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Homeotic genes (Hox) are universal regulators of the body patterning process in embryogenesis of metazoans. The Hox gene expression pattern (Hox code) retains in adult tissues and serves as a cellular positional identity marker. Despite previously existing notions that the Hox code is inherent in all stroma mesenchymal cells as a whole, recent studies have shown that the Hox code may be an attribute of a distinct subpopulation of adult resident mesenchymal stromal cells (MSC). Recent evidence allows suggesting a "non-canonical" role for Hox gene expression which is associated with renewal and regeneration in postnatal organs after damage. In tissues with high regenerative capacity, it has been shown that a special cell population is critical for these processes, a distinctive feature of which is the persistent expression of tissuespecific Hox genes. We believe that in the postnatal period Hox-positive subpopulation of resident MSC may serve as a unique regenerative reserve. These cells coordinate creation and maintenance of the correct structure of the stroma through a tissue-specific combination of mechanisms. In this article, we summarize data on the role of resident MSC with a tissue-specific pattern of Hox gene expression as regulators of correct tissue reconstruction after injury.

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“…BMAT is thought to be derived from bone marrow stromal (skeletal, mesenchymal) stem cells (BMSC) present within the bone marrow stroma and that are capable for differentiation, in addition to adipocytes, into osteoblasts and chondrocytes [1]. Currently, there is no consensus regarding the phenotype of BMAT progenitors but a number of markers have been proposed to identify adipocyte progenitors within the bone marrow, including osterix [4,5], Prx1 and Nestin1 (reviewed in [6]), leptin receptor [7], Rankl [8], Znf423 [9••], and Hoxa11 [10].…”

Section: Introductionmentioning

confidence: 99%

Insulin Signaling in Bone Marrow Adipocytes

Tencerová

Okla

Kassem

2019

Curr Osteoporos Rep

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Purpose of Review The goal of this review is to discuss the role of insulin signaling in bone marrow adipocyte formation, metabolic function, and its contribution to cellular senescence in relation to metabolic bone diseases. Recent Findings Insulin signaling is an evolutionally conserved signaling pathway that plays a critical role in the regulation of metabolism and longevity. Bone is an insulin-responsive organ that plays a role in whole body energy metabolism. Metabolic disturbances associated with obesity and type 2 diabetes increase a risk of fragility fractures along with increased bone marrow adiposity. In obesity, there is impaired insulin signaling in peripheral tissues leading to insulin resistance. However, insulin signaling is maintained in bone marrow microenvironment leading to hypermetabolic state of bone marrow stromal (skeletal) stem cells associated with accelerated senescence and accumulation of bone marrow adipocytes in obesity. Summary This review summarizes current findings on insulin signaling in bone marrow adipocytes and bone marrow stromal (skeletal) stem cells and its importance for bone and fat metabolism. Moreover, it points out to the existence of differences between bone marrow and peripheral fat metabolism which may be relevant for developing therapeutic strategies for treatment of metabolic bone diseases.with enhanced insulin sensitivity, glucose uptake, and oxidative phosphorylation. This metabolic phenotype of BMSC in obesity results in increased ROS production, which might lead to creation of senescent bone marrow microenvironment and stem cell exhaustion contributing to bone fragility in metabolic bone diseases Curr Osteoporos Rep (2019) 17:44 -454 6 447

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Hox11 expressing regional skeletal stem cells are progenitors for osteoblasts, chondrocytes and adipocytes throughout life

Cited by 88 publications

References 37 publications

Hox genes maintain critical roles in the adult skeleton

Hox genes maintain critical roles in the adult skeleton

Hox-Positive Adult Mesenchymal Stromal Cells: Beyond Positional Identity

Insulin Signaling in Bone Marrow Adipocytes

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