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Aging 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.

Urinary bladder dysfunction can be caused by environmental, genetic, and developmental insults. Depending upon insult severity, the bladder may lose its ability to maintain volumetric capacity and intravesical pressure resulting in renal deterioration. Bladder augmentation enterocystoplasty (BAE) is utilized to increase bladder capacity to preserve renal function using autologous bowel tissue as a “patch.” To avoid the clinical complications associated with this procedure, we have engineered composite grafts comprised of autologous bone marrow mesenchymal stem cells (MSCs) co-seeded with CD34+ hematopoietic stem/progenitor cells (HSPCs) onto a pliable synthetic scaffold [poly(1,8-octamethylene-citrate-co-octanol)(POCO)] or a biological scaffold (SIS; small intestinal submucosa) to regenerate bladder tissue in our baboon bladder augmentation model. We set out to determine the global protein expression profile of bladder tissue that has undergone regeneration with the aforementioned stem cell seeded scaffolds along with baboons that underwent BAE. Data demonstrate that POCO and SIS grafted animals share high protein homogeneity between native and regenerated tissues while BAE animals displayed heterogeneous protein expression between the tissues following long-term engraftment. We posit that stem cell-seeded scaffolds can recapitulate tissue that is nearly indistinguishable from native tissue at the protein level and may be used in lieu of procedures such as BAE.

Placental extracts have been reported to have anti-oxidative and anti-inflammatory activities. Because there is increasing evidence that ionizing radiation induces the release of reactive oxygen species (ROS) and inflammatory cytokines, we examined the protective effects of a placental extract against radiation injury. C57BL/6 mice were exposed to 1 Gy of γ-ray radiation every day for 5 days, and placental extract (1 mg/day) was administrated orally soon after each exposure. At 2 days after the last irradiation, mice were euthanized to examine the numbers, colony-forming capacity, and DNA damage of stem/progenitor cells in the peripheral blood and bone marrow. To understand the related mechanisms, we also measured the levels of intracellular and mitochondrial ROS, and 8-OHdG in the plasma and urine, and IL-6 and TNF-α in the plasma. Compared with the placebo treatment, oral administration of placental extract significantly increased the number and colony-forming capacity, but decreased the DNA damage of bone marrow stem/progenitor cells. However, neither the levels of intracellular and mitochondrial ROS in bone marrow cells, nor the levels of 8-OHdG in the urine and plasma significantly differed between groups. Interestingly, in comparison with the placebo treatment, placental extract significantly decreased the levels of the inflammatory cytokines IL-6 and TNF-α in the plasma. Placental extract significantly attenuated the acute radiation injury to bone marrow-derived stem/progenitor cells, and this protection is likely to be related to the anti-inflammatory activity of the placental extract.

This study presents an interim safety and feasibility analysis of the REGENERATE-IHD randomized controlled trial, which is examining the safety and efficacy of three different delivery routes of bone marrow-derived stem cells (BMSCs) in patients with ischemic heart failure. The first 58 patients recruited to the REGENERATE-IHD study are included in this interim analysis (pilot). Symptomatic patients with ischemic heart failure were randomized to receive subcutaneous granulocyte colony-stimulating factor or saline injections only; or subcutaneous granulocyte colony-stimulating factor injections followed by intracoronary or intramyocardial injections of BMSCs or serum (control). No significant differences were found in terms of safety and feasibility between the different delivery routes, with no significant difference in procedural complications or major adverse cardiac events. There was a signal towards improved heart failure symptoms in the patients treated with intramyocardial injection of mobilized BMSCs. Peripheral mobilization of BMSCs with or without subsequent direct myocardial delivery appears safe and feasible in patients with chronic ischemic heart failure.

Despite recent advances in pharmacologic and catheter‐based interventions for coronary heart disease, myocardial salvage is often incomplete resulting in a process of adverse left ventricular (LV) remodeling leading to symptomatic heart failure. This chapter discusses the relevance of cell therapy to interventional cardiology, outlining the progress of over a decade of clinical trials, and looks to future directions for clinical research. Studies in humans have confirmed that bone marrow mononuclear cells (BMNCs) and endothelial progenitor cells (EPC) are indeed mobilized from the bone marrow to sites of ischemia at the time of myocardial infarction. Mesenchymal stem cells (MSC) are stromal cells, found both in the bone marrow and adipose tissue. A randomized, blinded placebo‐controlled trial of 26 patients with chronic total arterial occlusions was conducted, where autologous granulocyte colony‐stimulating factor (G‐CSF) mobilized circulating progenitor cells were injected down percutaneously revascularized coronary arteries.

The authors acknowledge the financial support from the European Union Framework Programme for Research and Innovation HORIZON2020, under the TEAMING Grant agreement No 739572-The Discoveries CTR, the ERC Grant CoG MagTendon nr 772817, and the Achilles Grant nr 810850, FCT-Fundacao para a Ciencia e a Tecnologia for the PhD grant of IC (PD/BD/128088/2016); and the Project NORTE-01-0145-FEDER-000021: \"Accelerating tissue engineering and personalized medicine discoveries by the integration of key enabling nanotechnologies, marine-derived biomaterials and stem cells\", supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF).

Hematopoiesis is regulated by the bone marrow (BM) stroma. However, cellular identities and functions of the different BM stromal elements in humans remain poorly defined. Based on single-cell RNA sequencing (scRNAseq), we systematically characterized the human non-hematopoietic BM stromal compartment and we investigated stromal cell regulation principles based on the RNA velocity analysis using scVelo and studied the interactions between the human BM stromal cells and hematopoietic cells based on ligand-receptor (LR) expression using CellPhoneDB. scRNAseq led to the identification of six transcriptionally and functionally distinct stromal cell populations. Stromal cell differentiation hierarchy was recapitulated based on RNA velocity analysis and in vitro proliferation capacities and differentiation potentials. Potential key factors that might govern the transition from stem and progenitor cells to fate-committed cells were identified. In situ localization analysis demonstrated that different stromal cells were localized in different niches in the bone marrow. In silico cell-cell communication analysis further predicted that different stromal cell types might regulate hematopoiesis through distinct mechanisms. These findings provide the basis for a comprehensive understanding of the cellular complexity of the human BM microenvironment and the intricate stroma-hematopoiesis crosstalk mechanisms, thus refining our current view on human hematopoietic niche organization.

Current theory indicates that mitochondria were obtained 1.5 billion years ago from an ancient prokaryote. The mitochondria provided the capacity for aerobic respiration, the creation of the eukaryotic cell, and eventually complex multicellular organisms. Recent reports have found that mitochondria play essential roles in aging and determining lifespan. A variety of heritable and acquired diseases are linked to mitochondrial dysfunction. We report here that mitochondria are more dynamic than previously considered: mitochondria or mtDNA can move between cells. The active transfer from adult stem cells and somatic cells can rescue aerobic respiration in mammalian cells with nonfunctional mitochondria.

MicroRNAs (miRNAs) are a family of ≈22-nt noncoding RNAs that can posttranscriptionally regulate gene expression. Several miRNAs are specifically expressed in hematopoietic cells. Here we show that one such miRNA, miR-150, is mainly expressed in the lymph nodes and spleen and is highly up-regulated during the development of mature T and B cells; expression of miR-150 is sharply up-regulated at the immature B cell stage. Overexpression of miR-150 in hematopoietic stem cells, followed by bone marrow transplantation, had little effect on the formation of either mature CD8- and CD4-positive T cells or granulocytes or macrophages, but the formation of mature B cells was greatly impaired. Furthermore, premature expression of miR-150 blocked the transition from the pro-B to the pre-B stage. Our results indicate that miR-150 most likely down-regulates mRNAs that are important for pre- and pro-B cell formation or function, and its ectopic expression in these cells blocks further development of B cells. bone marrow transplantation hematopoiesis hematopoietic stem/progenitor cell lymphopoiesis

Myeloid cells are key components of the tumor microenvironment and critical regulators of disease progression. These innate immune cells are usually short-lived and require constant replenishment. Emerging evidence indicates that tumors alter the host hematopoietic system and induce the biased differentiation of myeloid cells to tip the balance of the systemic immune activities toward tumor-promoting functions. Altered myelopoiesis is not restricted to the bone marrow and also occurs in extramedullary organs. In this review, we outline the recent advances in the field of cancer-associated myelopoiesis, with a focus on the spleen, the major site of extramedullary hematopoiesis in the cancer setting. We discuss the functional specialization, distinct mechanisms, and clinical relevance of cancer-associated myeloid cell generation from early progenitors in the spleen and its potential as a novel therapeutic target.