Abstract:Although functional association between Wnt signaling and bone homeostasis has been well described through genetic ablation of Wntless (Wls), the mechanisms of how osteoblastic Wls regulates the fate of bone marrow stromal cells (BMSCs) and hematopoietic stem cells (HSCs) in relation to age are not yet understood. Here, we generated Col2.3-Cre;Wls fl/fl mice that were free from premature lethality and investigated age-related impacts of osteoblastic Wls deficiency on hematopoiesis, BM microenvironment, and mai… Show more
“…Long-term hyperglycemia is associated with impaired BM retention and functional defects in BM-derived stem cells, eventually resulting in abnormal hematopoiesis and bone mass accrual [ 9 , 11 , 35 ]. Similar to a previous report [ 31 ], the current findings indicate that the function and BM retention of MSCs are predominantly impaired compared with those of HSCs. It is demonstrated that trabecular bone is more impaired than cortical bone by hyperglycemic conditions.…”
Section: Discussionsupporting
confidence: 90%
“…Image slices were also reconstructed using cone-beam reconstruction software based on the Feldkamp algorithm (Dataviewer; Skyscan, Belgium). Values of bone-specific parameters, namely bone volume (BV, mm 3 ), bone volume percentage (BV/TV, %), bone mineral density (BMD; g/cm 3 ), trabecular number (Tb.N; 1/mm), and trabecular thickness (Tb.Th; mm) in trabecular and cortical regions of femoral bones were evaluated from the reconstructed 3D images, as described previously [ 31 ].…”
Section: Methodsmentioning
confidence: 99%
“…BM cells were collected by centrifugation (1000× g ) for 10 min and processed for the removal of red blood cells (RBCs). After washing with PBS, cells were analyzed by multicolor flow cytometry (BD Aria III, BD Biosciences, Franklin Lakes, NJ, USA), and phenotypical identification of cell populations was performed using FlowJo software (FLOWJO, Ashland, OR, USA) at the Center for University-Wide Research Facilities of Jeonbuk National University, as described previously [ 31 ]. In this study, BM LSK cells, Lin − Sca-1 − c-Kit + cells (hematopoietic progenitor cells, HPCs), and CD150 + CD48 − LSK cells (HSCs) were phenotypically identified after staining with lineage markers following phycoerythrin (PE)-Cy7-conjugated anti-CD3, anti-CD4, anti-CD8, anti-CD45R, anti-CD11b, anti-Gr-1, and anti-TER-119.…”
Hyperglycemia has various adverse health effects, some of which are due to chronic oxidative and inflammatory impairment of bone marrow (BM), hematopoietic stem cells (HSCs), and mesenchymal stem cells (MSCs). Astaxanthin (ASTX) has been shown to ameliorate hyperglycemia-associated systemic complications and acute mortality, and this effect is partially associated with restoration of normal hematopoiesis. Here, the effects of ASTX on diabetes-induced complications in BM and BM stem cells were investigated, and the underlying molecular mechanisms were elucidated. Ten-week-old C57BL/6 mice received a single intraperitoneal injection of streptozotocin (STZ; 150 mg/kg) in combination with oral gavage of ASTX (12.5 mg/kg) for 30 or 60 consecutive days. Supplemental ASTX ameliorated acute mortality and restored the STZ-impaired bone mass accrual and BM microenvironment in STZ-injected mice. Oral gavage of ASTX suppressed osteoclast formation in the BM of STZ-injected mice. Specifically, supplementation with ASTX inhibited oxidative stress and senescence induction of BM HSCs and MSCs and ameliorated hematopoietic disorders in STZ-injected mice. These effects of ASTX were associated with BM restoration of angiopoietin 1, stromal cell-derived factor 1, β-catenin, and Nrf2. Long-term ASTX gavage also recovered the STZ-induced dysfunction in migration, colony formation, and mineralization of BM-derived stromal cells. Further, a direct addition of ASTX exhibited direct and dose-dependent inhibition of osteoclastic activation without cytotoxic effects. Collectively, these results indicate that ASTX protects against diabetes-induced damage in the BM microenvironment in BM, HSCs, and MSCs and restores normal hematopoiesis and bone accrual in STZ-injected mice.
“…Long-term hyperglycemia is associated with impaired BM retention and functional defects in BM-derived stem cells, eventually resulting in abnormal hematopoiesis and bone mass accrual [ 9 , 11 , 35 ]. Similar to a previous report [ 31 ], the current findings indicate that the function and BM retention of MSCs are predominantly impaired compared with those of HSCs. It is demonstrated that trabecular bone is more impaired than cortical bone by hyperglycemic conditions.…”
Section: Discussionsupporting
confidence: 90%
“…Image slices were also reconstructed using cone-beam reconstruction software based on the Feldkamp algorithm (Dataviewer; Skyscan, Belgium). Values of bone-specific parameters, namely bone volume (BV, mm 3 ), bone volume percentage (BV/TV, %), bone mineral density (BMD; g/cm 3 ), trabecular number (Tb.N; 1/mm), and trabecular thickness (Tb.Th; mm) in trabecular and cortical regions of femoral bones were evaluated from the reconstructed 3D images, as described previously [ 31 ].…”
Section: Methodsmentioning
confidence: 99%
“…BM cells were collected by centrifugation (1000× g ) for 10 min and processed for the removal of red blood cells (RBCs). After washing with PBS, cells were analyzed by multicolor flow cytometry (BD Aria III, BD Biosciences, Franklin Lakes, NJ, USA), and phenotypical identification of cell populations was performed using FlowJo software (FLOWJO, Ashland, OR, USA) at the Center for University-Wide Research Facilities of Jeonbuk National University, as described previously [ 31 ]. In this study, BM LSK cells, Lin − Sca-1 − c-Kit + cells (hematopoietic progenitor cells, HPCs), and CD150 + CD48 − LSK cells (HSCs) were phenotypically identified after staining with lineage markers following phycoerythrin (PE)-Cy7-conjugated anti-CD3, anti-CD4, anti-CD8, anti-CD45R, anti-CD11b, anti-Gr-1, and anti-TER-119.…”
Hyperglycemia has various adverse health effects, some of which are due to chronic oxidative and inflammatory impairment of bone marrow (BM), hematopoietic stem cells (HSCs), and mesenchymal stem cells (MSCs). Astaxanthin (ASTX) has been shown to ameliorate hyperglycemia-associated systemic complications and acute mortality, and this effect is partially associated with restoration of normal hematopoiesis. Here, the effects of ASTX on diabetes-induced complications in BM and BM stem cells were investigated, and the underlying molecular mechanisms were elucidated. Ten-week-old C57BL/6 mice received a single intraperitoneal injection of streptozotocin (STZ; 150 mg/kg) in combination with oral gavage of ASTX (12.5 mg/kg) for 30 or 60 consecutive days. Supplemental ASTX ameliorated acute mortality and restored the STZ-impaired bone mass accrual and BM microenvironment in STZ-injected mice. Oral gavage of ASTX suppressed osteoclast formation in the BM of STZ-injected mice. Specifically, supplementation with ASTX inhibited oxidative stress and senescence induction of BM HSCs and MSCs and ameliorated hematopoietic disorders in STZ-injected mice. These effects of ASTX were associated with BM restoration of angiopoietin 1, stromal cell-derived factor 1, β-catenin, and Nrf2. Long-term ASTX gavage also recovered the STZ-induced dysfunction in migration, colony formation, and mineralization of BM-derived stromal cells. Further, a direct addition of ASTX exhibited direct and dose-dependent inhibition of osteoclastic activation without cytotoxic effects. Collectively, these results indicate that ASTX protects against diabetes-induced damage in the BM microenvironment in BM, HSCs, and MSCs and restores normal hematopoiesis and bone accrual in STZ-injected mice.
“…Recently, researchers led by Jeong‐Chae Lee and Sung‐Ho Kook (Jeonbuk National University, Jeonju, South Korea) explored how osteoblastic Wnt signaling regulates BM‐resident MSCs (or BMSCs) and HSCs during normal aging by examining mice following the loss of Wntless expression. Reporting in STEM CELLS , Poudel et al now provide evidence that interrupted osteoblastic Wnt signaling during aging differentially impacts these two important stem cell populations 4 . The authors generated a conditional knockout mouse model that permitted the osteoblast‐specific loss of Wntless expression and initially discovered that the interruption of Wnt signaling impaired the BM microenvironment and bone mass accrual.…”
Section: Featured Articlesmentioning
confidence: 99%
“…However, this information may allow for the identification of dysregulated components of the Wnt signaling cascade in cancer stem cells (CSCs) 3 and foster the development of therapeutic strategies that effectively inhibit tumorigenesis while safeguarding normal stem cell function. In our first Featured Article published this month in STEM CELLS , Poudel et al report that the loss of Wntless, which encodes a receptor for Wnt ligands in Wnt‐secreting cells, impairs the bone marrow (BM) microenvironment and differentially induces the senescence of mesenchymal stem cells (MSCs) and HSCs as a function of age 4 . In a Related Article published recently in STEM CELLS Translational Medicine , Khosla et al described the presence of liver CSC‐like cells in advanced cirrhosis patients that displayed enhanced tumor‐forming potential thanks to elevated levels of autocrine Wnt signaling 5 …”
Clonal hematopoiesis (CH) defines a premalignant state predominantly found in older persons that increases the risk of developing hematologic malignancies and age-related inflammatory diseases. However, the risk for malignant transformation or non-malignant disorders is variable and difficult to predict, and defining the clinical relevance of specific candidate driver mutations in individual carriers has proved to be challenging. In addition to the cell-intrinsic mechanisms, mutant cells rely on and alter cell-extrinsic factors from the bone marrow (BM) niche, which complicates the prediction of a mutant cell’s fate in a shifting pre-malignant microenvironment. Therefore, identifying the insidious and potentially broad impact of driver mutations on supportive niches and immune function in CH aims to understand the subtle differences that enable driver mutations to yield different clinical outcomes. Here, we review the changes in the aging BM niche and the emerging evidence supporting the concept that CH can progressively alter components of the local BM microenvironment. These alterations may have profound implications for the functionality of the osteo-hematopoietic niche and overall bone health, consequently fostering a conducive environment for the continued development and progression of CH. We also provide an overview of the latest technology developments to study the spatiotemporal dependencies in the CH BM niche, ideally in the context of longitudinal studies following CH over time. Finally, we discuss aspects of CH carrier management in clinical practice, based on work from our group and others.
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