Elevated hematopoietic stem cell frequency in mouse alveolar bone marrow.

Hematopoietic stem cells (HSCs) are crucial for maintaining hematopoietic homeostasis and are localized within distinct bone marrow (BM) niches. While BM niches are often considered similar across different skeletal sites, we discovered that the alveolar BM (al-BM) in the mandible harbors the highest frequency of immunophenotypic HSCs in nine different skeletal sites. Transplantation assays revealed significantly increased engraftment from al-BM compared to femur, tibia, or pelvis BM, likely due to a higher proportion of alveolar HSCs.

A maternal brain hormone that builds bone.

In lactating mothers, the high calcium (Ca) demand for milk production triggers significant bone loss. Although oestrogen normally counteracts excessive bone resorption by promoting bone formation, this sex steroid drops precipitously during this postpartum period. Here we report that brain-derived cellular communication network factor 3 (CCN3) secreted from KISS1 neurons of the arcuate nucleus (ARC) fills this void and functions as a potent osteoanabolic factor to build bone in lactating females.

Ultrasensitive and multiplexed tracking of single cells using whole-body PET/CT.

In vivo molecular imaging tools are crucially important for elucidating how cells move through complex biological systems; however, achieving single-cell sensitivity over the entire body remains challenging. Here, we report a highly sensitive and multiplexed approach for tracking upward of 20 single cells simultaneously in the same subject using positron emission tomography (PET). The method relies on a statistical tracking algorithm (PEPT-EM) to achieve a sensitivity of 4 becquerel per cell and a streamlined workflow to reliably label single cells with over 50 becquerel per cell of F-fluorodeoxyglucose (FDG).

Brain-Derived CCN3 Is An Osteoanabolic Hormone That Sustains Bone in Lactating Females.

In lactating mothers, the high calcium (Ca ) demand for milk production triggers significant bone resorption. While estrogen would normally counteract excessive bone loss and maintain sufficient bone formation during this postpartum period, this sex steroid drops precipitously after giving birth. Here, we report that brain-derived CCN3 (Cellular Communication Network factor 3) secreted from KISS1 neurons of the arcuate nucleus (ARC ) fills this void and functions as a potent osteoanabolic factor to promote bone mass in lactating females.

Efficient and multiplexed tracking of single cells using whole-body PET/CT.

molecular imaging tools are crucially important for elucidating how cells move through complex biological systems, however, achieving single-cell sensitivity over the entire body remains challenging. Here, we report a highly sensitive and multiplexed approach for tracking upwards of 20 single cells simultaneously in the same subject using positron emission tomography (PET). The method relies on a new tracking algorithm (PEPT-EM) to push the cellular detection threshold to below 4 Bq/cell, and a streamlined workflow to reliably label single cells with over 50 Bq/cell of F-fluorodeoxyglucose (FDG).

Del1 Is a Growth Factor for Skeletal Progenitor Cells in the Fracture Callus.

Failure to properly form bone or integrate surgical implants can lead to morbidity and additional surgical interventions in a significant proportion of orthopedic surgeries. While the role of skeletal stem cells (SSCs) in bone formation and repair is well-established, very little is known about the factors that regulate the downstream Bone, Cartilage, Stromal, Progenitors (BCSPs). BCSPs, as transit amplifying progenitor cells, undergo multiple mitotic divisions to expand the pool of lineage committed progenitors allowing stem cells to preserve their self-renewal and stemness.

Gla-domain mediated targeting of externalized phosphatidylserine for intracellular delivery.

Phosphatidylserine (PS) is a negatively charged phospholipid normally localized to the inner leaflet of the plasma membrane of cells but is externalized onto the cell surface during apoptosis as well as in malignant and infected cells. Consequently, PS may comprise an important molecular target in diagnostics, imaging, and targeted delivery of therapeutic agents. While an array of PS-binding molecules exist, their utility has been limited by their inability to internalize diagnostic or therapeutic payloads.

Purification and functional characterization of novel human skeletal stem cell lineages.

Human skeletal stem cells (hSSCs) hold tremendous therapeutic potential for developing new clinical strategies to effectively combat congenital and age-related musculoskeletal disorders. Unfortunately, refined methodologies for the proper isolation of bona fide hSSCs and the development of functional assays that accurately recapitulate their physiology within the skeleton have been lacking. Bone marrow-derived mesenchymal stromal cells (BMSCs), commonly used to describe the source of precursors for osteoblasts, chondrocytes, adipocytes and stroma, have held great promise as the basis of various approaches for cell therapy.

Optimizing Delivery of Therapeutic Growth Factors for Bone and Cartilage Regeneration.

Bone- and cartilage-related diseases, such as osteoporosis and osteoarthritis, affect millions of people worldwide, impairing their quality of life and increasing mortality. Osteoporosis significantly increases the bone fracture risk of the spine, hip, and wrist. For successful fracture treatment and to facilitate proper healing in the most complicated cases, one of the most promising methods is to deliver a therapeutic protein to accelerate bone regeneration.

A Combination of Distinct Vascular Stem/Progenitor Cells for Neovascularization and Ischemic Rescue.

Background: Peripheral vascular disease remains a leading cause of vascular morbidity and mortality worldwide despite advances in medical and surgical therapy. Besides traditional approaches, which can only restore blood flow to native arteries, an alternative approach is to enhance the growth of new vessels, thereby facilitating the physiological response to ischemia.

Methods: The Actin/R26 Rainbow reporter mouse was used for unbiased in vivo survey of injury-responsive vasculogenic clonal formation.

Denervation during mandibular distraction osteogenesis results in impaired bone formation.

Mandibular distraction osteogenesis (DO) is mediated by skeletal stem cells (SSCs) in mice, which enact bone regeneration via neural crest re-activation. As peripheral nerves are essential to progenitor function during development and in response to injury, we questioned if denervation impairs mandibular DO. C57Bl6 mice were divided into two groups: DO with a segmental defect in the inferior alveolar nerve (IAN) at the time of mandibular osteotomy ("DO Den") and DO with IAN intact ("DO Inn").

A seed-and-soil theory for blood ageing.

The bone marrow is the daily production site for hundreds of billions of blood cells. A new study adds evidence that, during ageing, signals emanating from bone-marrow stromal cells shift to produce inflammatory factors that skew blood-cell output, driving age-related tissue deterioration.

Sexually dimorphic estrogen sensing in skeletal stem cells controls skeletal regeneration.

Sexually dimorphic tissues are formed by cells that are regulated by sex hormones. While a number of systemic hormones and transcription factors are known to regulate proliferation and differentiation of osteoblasts and osteoclasts, the mechanisms that determine sexually dimorphic differences in bone regeneration are unclear. To explore how sex hormones regulate bone regeneration, we compared bone fracture repair between adult male and female mice.

Cross-species comparisons reveal resistance of human skeletal stem cells to inhibition by non-steroidal anti-inflammatory drugs.

Fracture healing is highly dependent on an early inflammatory response in which prostaglandin production by cyclo-oxygenases (COX) plays a crucial role. Current patient analgesia regimens favor opioids over Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) since the latter have been implicated in delayed fracture healing. While animal studies broadly support a deleterious role of NSAID treatment to bone-regenerative processes, data for human fracture healing remains contradictory.

Aging of Skeletal Stem Cells.

The skeletal system is generated and maintained by its progenitors, skeletal stem cells (SSCs), across the duration of life. Gradual changes associated with aging result in significant differences in functionality of SSCs. Declines in bone and cartilage production, increase of bone marrow adipose tissue, compositional changes of cellular microenvironments, and subsequent deterioration of external and internal structures culminate in the aged and weakened skeleton.

The Tabula Sapiens: A multiple-organ, single-cell transcriptomic atlas of humans.

Molecular characterization of cell types using single-cell transcriptome sequencing is revolutionizing cell biology and enabling new insights into the physiology of human organs. We created a human reference atlas comprising nearly 500,000 cells from 24 different tissues and organs, many from the same donor. This atlas enabled molecular characterization of more than 400 cell types, their distribution across tissues, and tissue-specific variation in gene expression.

Skeletal Stem Cells as the Developmental Origin of Cellular Niches for Hematopoietic Stem and Progenitor Cells.

The skeletal system is a highly complex network of mesenchymal, hematopoietic, and vasculogenic stem cell lineages that coordinate the development and maintenance of defined microenvironments, so-called niches. Technological advancements in recent years have allowed for the dissection of crucial cell types as well as their autocrine and paracrine signals that regulate these niches during development, homeostasis, regeneration, and disease. Ingress of blood vessels and bone marrow hematopoiesis are initiated by skeletal stem cells (SSCs) and their more committed downstream lineage cell types that direct shape and form of skeletal elements.

Aged skeletal stem cells generate an inflammatory degenerative niche.

Loss of skeletal integrity during ageing and disease is associated with an imbalance in the opposing actions of osteoblasts and osteoclasts. Here we show that intrinsic ageing of skeletal stem cells (SSCs) in mice alters signalling in the bone marrow niche and skews the differentiation of bone and blood lineages, leading to fragile bones that regenerate poorly. Functionally, aged SSCs have a decreased bone- and cartilage-forming potential but produce more stromal lineages that express high levels of pro-inflammatory and pro-resorptive cytokines.

Skeletal stem and progenitor cells maintain cranial suture patency and prevent craniosynostosis.

Cranial sutures are major growth centers for the calvarial vault, and their premature fusion leads to a pathologic condition called craniosynostosis. This study investigates whether skeletal stem/progenitor cells are resident in the cranial sutures. Prospective isolation by FACS identifies this population with a significant difference in spatio-temporal representation between fusing versus patent sutures.

Prrx1 Fibroblasts Represent a Pro-fibrotic Lineage in the Mouse Ventral Dermis.

Fibroblast heterogeneity has been shown within the unwounded mouse dorsal dermis, with fibroblast subpopulations being identified according to anatomical location and embryonic lineage. Using lineage tracing, we demonstrate that paired related homeobox 1 (Prrx1)-expressing fibroblasts are responsible for acute and chronic fibroses in the ventral dermis. Single-cell transcriptomics further corroborated the inherent fibrotic characteristics of Prrx1 fibroblasts during wound repair.

Articular cartilage regeneration by activated skeletal stem cells.

Osteoarthritis (OA) is a degenerative disease resulting in irreversible, progressive destruction of articular cartilage. The etiology of OA is complex and involves a variety of factors, including genetic predisposition, acute injury and chronic inflammation. Here we investigate the ability of resident skeletal stem-cell (SSC) populations to regenerate cartilage in relation to age, a possible contributor to the development of osteoarthritis.