Distinct skeletal stem cell types orchestrate long bone skeletogenesis.

Skeletal stem and progenitor cell populations are crucial for bone physiology. Characterization of these cell types remains restricted to heterogenous bulk populations with limited information on whether they are unique or overlap with previously characterized cell types. Here we show, through comprehensive functional and single-cell transcriptomic analyses, that postnatal long bones of mice contain at least two types of bone progenitors with bona fide skeletal stem cell (SSC) characteristics.

Delayed Union of a Diaphyseal Forearm Fracture Associated With Impaired Osteogenic Differentiation of Prospectively Isolated Human Skeletal Stem Cells.

Delayed union or nonunion are relatively rare complications after fracture surgery, but when they do occur, they can result in substantial morbidity for the patient. In many cases, the etiology of impaired fracture healing is uncertain and attempts to determine the molecular basis for delayed union and nonunion formation have been limited. Prospectively isolating skeletal stem cells (SSCs) from fracture tissue samples at the time of surgical intervention represent a feasible methodology to determine a patient's biologic risk for compromised fracture healing.

Therapeutic modulation of phagocytosis in glioblastoma can activate both innate and adaptive antitumour immunity.

Tumour cell phagocytosis by antigen presenting cells (APCs) is critical to the generation of antitumour immunity. However, cancer cells can evade phagocytosis by upregulating anti-phagocytosis molecule CD47. Here, we show that CD47 blockade alone is inefficient in stimulating glioma cell phagocytosis.

Improving immune-vascular crosstalk for cancer immunotherapy.

The vasculature of tumours is highly abnormal and dysfunctional. Consequently, immune effector cells have an impaired ability to penetrate solid tumours and often exhibit compromised functions. Normalization of the tumour vasculature can enhance tissue perfusion and improve immune effector cell infiltration, leading to immunotherapy potentiation.

Immune Priming of the Tumor Microenvironment by Radiation.

Ionizing irradiation can induce a multitude of alterations within the tumor microenvironment. Unlike targeted therapies, radiation delivered to the tumor bed can prompt phenotypic changes in both normal stromal and cancer cells, leading to molecular and physiological alterations within the tumor microenvironment. These environmental modulations directly influence the degree of immunogenicity of the tumor microenvironment and may ultimately affect tumor responsiveness to cancer immunotherapies.

Brief Report: External Beam Radiation Therapy for the Treatment of Human Pluripotent Stem Cell-Derived Teratomas.

Human pluripotent stem cells, including human embryonic stem cells (hESCs) and human induced PSCs (hiPSCs), have great potential as an unlimited donor source for cell-based therapeutics. The risk of teratoma formation from residual undifferentiated cells, however, remains a critical barrier to the clinical application of these cells. Herein, we describe external beam radiation therapy (EBRT) as an attractive option for the treatment of this iatrogenic growth.

Lessons from immuno-oncology: a new era for cancer nanomedicine?

Despite a decade of intensive preclinical research, the translation of cancer nanomedicine to the clinic has been slow. Here, we discuss how recent lessons learned from the successes with immuno-oncology therapies could be applied to cancer nanomedicine and how this may help to overcome some of the key technical challenges in this field.

Pharmacological rescue of diabetic skeletal stem cell niches.

Diabetes mellitus (DM) is a metabolic disease frequently associated with impaired bone healing. Despite its increasing prevalence worldwide, the molecular etiology of DM-linked skeletal complications remains poorly defined. Using advanced stem cell characterization techniques, we analyzed intrinsic and extrinsic determinants of mouse skeletal stem cell (mSSC) function to identify specific mSSC niche-related abnormalities that could impair skeletal repair in diabetic (Db) mice.

Lectins bring benefits to bones.

The discovery that proteins called c-type lectins promote bone growth could lead to new treatments for age-related bone disorders.

Local and Circulating Endothelial Cells Undergo Endothelial to Mesenchymal Transition (EndMT) in Response to Musculoskeletal Injury.

Endothelial-to-mesenchymal transition (EndMT) has been implicated in a variety of aberrant wound healing conditions. However, unambiguous evidence of EndMT has been elusive due to limitations of in vitro experimental designs and animal models. In vitro experiments cannot account for the myriad ligands and cells which regulate differentiation, and in vivo tissue injury models may induce lineage-independent endothelial marker expression in mesenchymal cells.

Breaking Down the Barriers to Precision Cancer Nanomedicine.

Nanomedicine offers unique advantages in treating human cancers. However, physiological and pathological barriers within normal and disease tissues, which are highly variable among individuals, often hinder its effectiveness. The body possesses specific innate responses to nanoparticles (NPs), which when combined with unique pathophysiological signatures in the tumor microenvironment, can severely limit the utility of nanomedicine in the oncological setting.

Evaluation of the physician quality improvement initiative: the expected and unexpected opportunities.

Background: The Physician Quality Improvement Initiative (PQII) uses a well-established multi-source feedback program, and incorporates an additional facilitated feedback review with their department chief. The purpose of this mixed methods study was to examine the value of the PQII by eliciting feedback from various stakeholders.

Methods: All participants and department chiefs (n = 45) were invited to provide feedback on the project implementation and outcomes via survey and/or an interview.

Enrichment of Adipose-Derived Stromal Cells for BMPR1A Facilitates Enhanced Adipogenesis.

Background: Reconstruction of soft tissue defects has traditionally relied on the use of grafts and flaps, which may be associated with variable resorption and/or significant donor site morbidity. Cell-based strategies employing adipose-derived stromal cells (ASCs), found within the stromal vascular fraction (SVF) of adipose tissue, may offer an alternative strategy for soft tissue reconstruction. In this study, we investigated the potential of a bone morphogenetic protein receptor type 1A (BMPR1A)(+) subpopulation of ASCs to enhance de novo adipogenesis.

Identification and characterization of an injury-induced skeletal progenitor.

The postnatal skeleton undergoes growth, remodeling, and repair. We hypothesized that skeletal progenitor cells active during these disparate phases are genetically and phenotypically distinct. We identified a highly potent regenerative cell type that we term the fracture-induced bone, cartilage, stromal progenitor (f-BCSP) in the fracture callus of adult mice.

Identification and specification of the mouse skeletal stem cell.

How are skeletal tissues derived from skeletal stem cells? Here, we map bone, cartilage, and stromal development from a population of highly pure, postnatal skeletal stem cells (mouse skeletal stem cells, mSSCs) to their downstream progenitors of bone, cartilage, and stromal tissue. We then investigated the transcriptome of the stem/progenitor cells for unique gene-expression patterns that would indicate potential regulators of mSSC lineage commitment. We demonstrate that mSSC niche factors can be potent inducers of osteogenesis, and several specific combinations of recombinant mSSC niche factors can activate mSSC genetic programs in situ, even in nonskeletal tissues, resulting in de novo formation of cartilage or bone and bone marrow stroma.

Osteoclast derivation from mouse bone marrow.

Osteoclasts are highly specialized cells that are derived from the monocyte/macrophage lineage of the bone marrow. Their unique ability to resorb both the organic and inorganic matrices of bone means that they play a key role in regulating skeletal remodeling. Together, osteoblasts and osteoclasts are responsible for the dynamic coupling process that involves both bone resorption and bone formation acting together to maintain the normal skeleton during health and disease.

Epigenetic and in vivo comparison of diverse MSC sources reveals an endochondral signature for human hematopoietic niche formation.

In the last decade there has been a rapid expansion in clinical trials using mesenchymal stromal cells (MSCs) from a variety of tissues. However, despite similarities in morphology, immunophenotype, and differentiation behavior in vitro, MSCs sourced from distinct tissues do not necessarily have equivalent biological properties. We performed a genome-wide methylation, transcription, and in vivo evaluation of MSCs from human bone marrow (BM), white adipose tissue, umbilical cord, and skin cultured in humanized media.

Highly permeable silicon membranes for shear free chemotaxis and rapid cell labeling.

Microfluidic systems are powerful tools for cell biology studies because they enable the precise addition and removal of solutes in small volumes. However, the fluid forces inherent in the use of microfluidics for cell cultures are sometimes undesirable. An important example is chemotaxis systems where fluid flow creates well-defined and steady chemotactic gradients but also pushes cells downstream.

Do pluripotent stem cells exist in adult mice as very small embryonic stem cells?

Very small embryonic-like stem cells (VSELs) isolated from bone marrow (BM) have been reported to be pluripotent. Given their nonembryonic source, they could replace blastocyst-derived embryonic stem cells in research and medicine. However, their multiple-germ-layer potential has been incompletely studied.

BLT-humanized C57BL/6 Rag2-/-γc-/-CD47-/- mice are resistant to GVHD and develop B- and T-cell immunity to HIV infection.

The use of C57BL/6 Rag2(-/-)γc(-/-) mice as recipients for xenotransplantation with human immune systems (humanization) has been problematic because C57BL/6 SIRPα does not recognize human CD47, and such recognition is required to suppress macrophage-mediated phagocytosis of transplanted human hematopoietic stem cells (HSCs). We show that genetic inactivation of CD47 on the C57BL/6 Rag2(-/-)γc(-/-) background negates the requirement for CD47-signal recognition protein α (SIRPα) signaling and induces tolerance to transplanted human HSCs. These triple-knockout, bone marrow, liver, thymus (TKO-BLT) humanized mice develop organized lymphoid tissues including mesenteric lymph nodes, splenic follicles and gut-associated lymphoid tissue that demonstrate high levels of multilineage hematopoiesis.

Clonal precursor of bone, cartilage, and hematopoietic niche stromal cells.

Organs are composites of tissue types with diverse developmental origins, and they rely on distinct stem and progenitor cells to meet physiological demands for cellular production and homeostasis. How diverse stem cell activity is coordinated within organs is not well understood. Here we describe a lineage-restricted, self-renewing common skeletal progenitor (bone, cartilage, stromal progenitor; BCSP) isolated from limb bones and bone marrow tissue of fetal, neonatal, and adult mice.

Canadian practice assessment in chronic obstructive pulmonary disease: respiratory specialist physician perception versus patient reality.

Introduction: Chronic obstructive pulmonary disease (COPD) is a common respiratory condition and the fourth leading cause of death in Canada. Optimal COPD management requires patients to participate in their care and physician knowledge of patients' perceptions of their disease.

Methods: A prospective study in which respiratory specialist physicians completed a practice assessment questionnaire and patient assessments for 15 to 20 consecutive patients with COPD.

Rationale for earlier treatment in COPD: a systematic review of published literature in mild-to-moderate COPD.

COPD is progressive and typically begins many years before a definite diagnosis is made. As the rate of decline in lung function may be faster in the initial stages of the disease, early intervention could be beneficial to control symptoms and affect disease progression and outcomes. A systematic review of published literature relating to mild-to-moderate COPD (patients with FEV(1) ≥50% predicted) was performed to evaluate the level of impairment and natural history or disease progression over time, and impact of interventions on the outcomes of patients with early-stage disease.

In vivo directed differentiation of pluripotent stem cells for skeletal regeneration.

Pluripotent cells represent a powerful tool for tissue regeneration, but their clinical utility is limited by their propensity to form teratomas. Little is known about their interaction with the surrounding niche following implantation and how this may be applied to promote survival and functional engraftment. In this study, we evaluated the ability of an osteogenic microniche consisting of a hydroxyapatite-coated, bone morphogenetic protein-2-releasing poly-L-lactic acid scaffold placed within the context of a macroenvironmental skeletal defect to guide in vivo differentiation of both embryonic and induced pluripotent stem cells.