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Potential cellular and molecular mechanism(s) of recovery/regeneration of damaged bone marrow sinusoidal endothelial cells (BM SECs). BM SECs may recover following damage through the ability of self-repair and proliferation of preexisting SECs. Moreover, haematopoietic stem cells (HSCs) may speed up the recovery/regeneration via providing angiogenic factors and triggering vascular endothelial growth factor (VEGF)/VEGF receptor (VEGR) and angiopoietin-1 (Ang-1)/Tie2 signalling pathways in SECs. HSCs may also be able to transdifferentiate into either endothelial progenitor cells (EPCs) and/or SECs which result in improving the recovery/regeneration of damaged sinusoids. In addition, EPCs (circulating ones and/or those residing in bone marrow) might be able to differentiate into SECs and also can produce angiogenic factors for damaged SECs. Finally, haematopoietic cells (HCs) within the bone marrow can release a wide range of growth factors and chemokines which can directly and/or indirectly improve the recovery/regeneration of damaged sinusoids

Potential cellular and molecular mechanism(s) of recovery/regeneration of damaged bone marrow sinusoidal endothelial cells (BM SECs). BM SECs may recover following damage through the ability of self-repair and proliferation of preexisting SECs. Moreover, haematopoietic stem cells (HSCs) may speed up the recovery/regeneration via providing angiogenic factors and triggering vascular endothelial growth factor (VEGF)/VEGF receptor (VEGR) and angiopoietin-1 (Ang-1)/Tie2 signalling pathways in SECs. HSCs may also be able to transdifferentiate into either endothelial progenitor cells (EPCs) and/or SECs which result in improving the recovery/regeneration of damaged sinusoids. In addition, EPCs (circulating ones and/or those residing in bone marrow) might be able to differentiate into SECs and also can produce angiogenic factors for damaged SECs. Finally, haematopoietic cells (HCs) within the bone marrow can release a wide range of growth factors and chemokines which can directly and/or indirectly improve the recovery/regeneration of damaged sinusoids

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It is very well known that bone marrow (BM) microvasculature may possess a crucial role in the maintenance of homeostasis of BM due to mutual interactions between BM microvascular system and other physiological functions including haematopoiesis and osteogenesis. Chemotherapy and radiotherapy are known as main approaches for cancer treatment and al...

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... Currently there are insufficient studies to investigate the extent of the contribution of both bone marrow and non-bone marrow derived macrophages in wound healing. Previous studies have reported that chemotherapy and/or irradiation can cause significant bone marrow damage, leading to delay in hematopoiesis recovery and, thus, migration of monocytes into the circulation [57][58][59][60]. Therefore, it is important to interrogate whether non-bone marrow derived macrophages can compensate the delay in migration of circulating monocytes into the injury sites to regulate wound healing. ...
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Macrophages are key immune cells that respond to infections, and modulate pathophysiological conditions such as wound healing. By possessing phagocytic activities and through the secretion of cytokines and growth factors, macrophages are pivotal orchestrators of inflammation, fibrosis, and wound repair. Macrophages orchestrate the process of wound healing through the transitioning from predominantly pro-inflammatory (M1-like phenotypes), which present early post-injury, to anti-inflammatory (M2-like phenotypes), which appear later to modulate skin repair and wound closure. In this review, different cellular and molecular aspects of macrophage-mediated skin wound healing are discussed, alongside important aspects such as macrophage subtypes, metabolism, plasticity, and epigenetics. We also highlight previous studies demonstrating interactions between macrophages and these factors for optimal wound healing. Understanding and harnessing the activity and capability of macrophages may help to advance new approaches for improving healing of the skin.
... Endothelial cells (EC) are responsible for tissue growth and regeneration under homeostasis and stress in multiple organs. 2 In the hematopoietic system, EC are an important constituent of the bone marrow (BM) microenvironment and play an essential role in regulating hematopoietic stem cell (HSC) homeostasis. [3][4][5][6] Besides affecting malignant cells, chemo-radiotherapy also damages both HSC and their supportive BM microenvironment, especially EC. 4,[7][8][9][10][11][12] As a result, BM EC damage, with a high level of apoptosis and a sustained state of inflammation, limits the recovery of hematopoiesis after chemo-radiotherapy, 4,9,10,[13][14][15][16][17][18] whereas inhibition of EC apoptosis or an infusion of EC accelerates hematopoietic recovery, 10,18,19 indicating that BM EC are a prerequisite for hematopoietic recovery. It is, therefore, critical to identify the mechanism(s) underlying BM EC damage in order to be able to promote hematopoietic recovery. ...
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Bone marrow(BM) endothelial progenitor cell(EPC) damage with unknown mechanism delays the repair of endothelial cells(ECs) and hematopoiesis recovery after chemo-radiotherapy. Herein, enhanced glycolytic enzyme PFKFB3 was demonstrated in the damaged BM EPCs of patients with poor graft function(PGF), a clinical model of EPC damage-associated poor hematopoiesis after allogeneic hematopoietic stem cell transplantation(allo-HSCT). Moreover, glycolysis inhibitor 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one(3PO) alleviated the damaged BM EPCs of PGF patients in vitro. Consistently, PFKFB3 overexpression triggered BM EPC damage after 5FU treatment and impaired hematopoiesis-supporting ability in vitro. Mechanismly, PFKFB3 facilitated pro-apoptotic transcription factor FOXO3A and its downstream gene expressions, including p21, p27, FAS after 5FU treatment in vitro. Moreover, PFKFB3 induced NF-κB activation and its downstream adhesion molecule E-selectin expression, while reduced hematopoietic factor SDF-1 expression, which could be rescued by FOXO3A silence. Highly expressed PFKFB3 was found in damaged BM ECs of chemo-radiotherapy-induced myelosuppression murine models. Furthermore, the BM EC-specific PFKFB3 overexpression murine model demonstrated that PFKFB3 aggravated BM EC damage, and impaired hematopoiesis recovery after chemotherapy in vivo, which could be improved by 3PO, indicating a critical role of PFKFB3 in regulating BM EC damage. Clinically, PFKFB3-induced FOXO3A expression and NF-κB activation were confirmed to contribute to the damaged BM EPCs of patients with acute leukemia after chemotherapy. 3PO repaired the damaged BM EPCs by reducing FOXO3A expression and phospho-NF-κB p65 in patients after chemotherapy. In summary, our results reveal a critical role of PFKFB3 in triggering BM EPC damage and indicate that endothelial-PFKFB3 may be a potential therapeutic target for myelosuppressive injury.
... About 80% are located near the sinusoids, which are irregular tubular spaces for the passage of blood that supplant capillaries and venules in the bone marrow, a.k.a., the BM microvascular system [12]. Bone marrow sinusoidal endothelium damage caused by chemotherapy or irradiation is often accompanied by destruction of the sinusoidal vasculature [13]. The infusion of vascular endothelial/progenitor cells allows for recovery of the sinusoidal vasculature, leading to hematopoietic reconstruction [14]. ...
Article
Background: Irradiation disrupts the vascular niche where hematopoietic stem cells (HSCs) reside, causing delayed hematopoietic reconstruction. The subsequent recovery of sinusoidal vessels is key to vascular niche regeneration and a prerequisite for hematopoietic reconstruction. We hypothesize that resident bone marrow macrophages (BM-Mφs) are responsible for repairing the HSC niche upon irradiation injury. Methods: We examined the survival and activation of BM-Mφs in C57BL/6 mice upon total body irradiation. After BM-Mφ depletion via injected clodronate-containing liposomes and irradiation injury, hematopoietic reconstruction and sinusoidal vascular regeneration were assessed with immunofluorescence and flow cytometry. Then enzyme-linked immunosorbent assay (ELISA) and flow cytometry were performed to analyze the contribution of VEGF-A released by BM-Mφs to the vascular restructuring of the HSC niche. VEGF-A-mediated signal transduction was assessed with transcriptome sequencing, flow cytometry, and pharmacology (agonists and antagonists) to determine the molecular mechanisms of Piezo1-mediated responses to structural changes in the HSC niche. Results: The depletion of BM-Mφs aggravated the post-irradiation injury, delaying the recovery of sinusoidal endothelial cells and HSCs. A fraction of the BM-Mφ population persisted after irradiation, with residual BM-Mφ exhibiting an activated M2-like phenotype. The expression of VEGF-A, which is essential for sinusoidal regeneration, was upregulated in BM-Mφs post-irradiation, especially CD206+ BM-Mφs. The expression of mechanosensory ion channel Piezo1, a response to mechanical environmental changes induced by bone marrow ablation, was upregulated in BM-Mφs, especially CD206+ BM-Mφs. Piezo1 upregulation was mediated by the effects of irradiation, the activation of Piezo1 itself, and the M2-like polarization induced by the phagocytosis of apoptotic cells. Piezo1 activation was associated with increased expression of VEGF-A and increased accumulation of NFATC1, NFATC2, and HIF-1α. The Piezo1-mediated upregulation in VEGF-A was suppressed by inhibiting the calcineurin/NFAT/HIF-1α signaling pathway. Conclusion: These findings reveal that BM-Mφs play a critical role in promoting vascular niche regeneration by sensing and responding to structural changes after irradiation injury, offering a potential target for therapeutic efforts to enhance hematopoietic reconstruction.
... 15 In long bones, arteries pass through bone canals entering the BM cavity and branch into a multitude of arterioles, capillaries, and sinusoids creating a vascularized BM region. 14,16 The BM microvasculature supplies oxygen and nutrients and removes metabolic waste from the extensively productive BM. Furthermore, mature blood cells leave the BM to the systemic circulation through the sinusoids. ...
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Hematopoietic stem and progenitor cells maintain hematopoiesis throughout life by generating all major blood cell lineages through the process of self-renewal and differentiation. In adult mammals, hematopoietic stem cells (HSCs) primarily reside in the bone marrow (BM) at special microenvironments called "niches." Niches are thought to extrinsically orchestrate the HSC fate including their quiescence and proliferation. Insight into the HSC niches mainly comes from studies in mice using surface marker identification and imaging to visualize HSC localization and association with niche cells. The advantage of mouse models is the possibility to study the 3-dimensional BM architecture and cell interactions in an intact traceable system. However, this may not be directly translational to human BM. Sedentary lifestyle, unhealthy diet, excessive alcohol intake, and smoking are all known risk factors for various diseases including hematological disorders and cancer, but how do lifestyle factors impact hematopoiesis and the associated niches? Here, we review current knowledge about the HSC niches and how unhealthy lifestyle may affect it. In addition, we summarize epidemiological data concerning the influence of lifestyle factors on hematological disorders and malignancies.
... intrinsic reason for the differences remains to be clarified, but some studies proposed that it might be because the biological property of bone metastases caused less systematic failures (25,(29)(30)(31). Thus patients could survive with better physical condition and tolerate surgical therapy with the subsequent potential complications. ...
Article
Background: There is a heated debate on whether or not a late-stage cancer patient with bone metastasis should receive primary surgery. The aim was to assess whether primary tumor surgery in cancer patients with bone metastasis was associated with improved survival. Methods: Cancer patients with bone metastasis were identified in the Surveillance, Epidemiology, and End Results database between 2010 and 2016. Overall survival and cancer-specific survival were compared between patients with and without primary tumor surgery using risk-adjusted Cox proportional hazard regression models and stratified propensity score methods. Further nomograms were constructed to predict personalized survival. Results: Overall, 22,631 cancer patients with synchronous bone metastasis were identified and the surgery rates were 33.3%, 76.3%, 42.0% and 2.0% for breast, bladder, renal and lung cancer, respectively. In Cox regression analysis after propensity score matching, primary cancer surgery was associated with a significantly improved overall survival for breast [hazard ratio (HR) =0.56], bladder (HR =0.69), lung (HR =0.61) and renal carcinoma (HR =0.37), while the prolonged median survival time was 20 months, 3 months, 4months and 21 months, respectively. Nomograms were constructed based on predictive factors, showing good consistency between the actual and predicted outcomes (C-index between 0.697 to 0.750) and feasibility in clinical practice. Conclusions: This population-based cohort of cancer patients with bone metastasis supports primary tumor surgery as a significant protective factor for cancer patients with bone metastasis, and nomograms hold promise in assisting individualized risk stratification and accurate therapeutic strategy making.
... EPC can differentiate into endothelial cells and promote the repair of injured vascular niche, indicating its important role in hematopoietic reconstruction [13]. Under normal conditions, mature vascular endothelium is in a stable quiescent state, but under pathological conditions, the vascular endothelium is detached, leading to morphology changes, increased vascular permeability and vascular fibrosis [14][15][16]. We previously found that preconditioning regimens prior to HSCT could cause damage to vascular endothelial structure and function and changes in endothelial permeability [17][18][19]. ...
... We previously found that preconditioning regimens prior to HSCT could cause damage to vascular endothelial structure and function and changes in endothelial permeability [17][18][19]. However, the current underlying mechanisms of endothelial injury and strategies to promote endothelial repair during preconditioning treatment are still lacking [14]. ...
... Bone marrow microvascular endothelial cells are an important part of the bone marrow microenvironment and play an important role in maintaining bone marrow homeostasis and promoting hematopoietic reconstruction [12,31,32]. A large number of data have proved that radiotherapy and chemotherapy can cause severe damage to bone marrow microvascular endothelium [14,33]. However, there are few reports on the underlying mechanism of endothelial injury and promoting bone marrow endothelial injury repair strategies after radiotherapy and chemotherapy. ...
Article
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Background: Preconditioning before bone marrow transplantation such as irradiation causes vascular endothelial cells damage and promoting the repair of damaged endothelial cells is beneficial for hematopoietic reconstitution. Pigment epithelium-derived factor (PEDF) regulates vascular permeability. However, PEDF's role in the repair of damaged endothelial cells during preconditioning remains unclear. The purpose of our study is to investigate PEDF's effect on preconditioning-induced damage of endothelial cells and hematopoietic reconstitution. Methods: Damaged endothelial cells induced by irradiation was co-cultured with hematopoietic stem cells (HSC) in the absence or presence of PEDF followed by analysis of HSC number, cell cycle, colony formation and differentiation. In addition, PEDF was injected into mice model of bone marrow transplantation followed by analysis of bone marrow injury, HSC number and peripheral hematopoietic reconstitution as well as the secretion of cytokines (SCF, TGF-β, IL-6 and TNF-α). Comparisons between two groups were performed by student t-test and multiple groups by one-way or two-way ANOVA. Results: Damaged endothelial cells reduced HSC expansion and colony formation, induced HSC cell cycle arrest and apoptosis and promoted HSC differentiation as well as decreased PEDF expression. Addition of PEDF increased CD144 expression in damaged endothelial cells and inhibited the increase of endothelial permeability, which were abolished after addition of PEDF receptor inhibitor Atglistatin. Additionally, PEDF ameliorated the inhibitory effect of damaged endothelial cells on HSC expansion in vitro. Finally, PEDF accelerated hematopoietic reconstitution after bone marrow transplantation in mice and promoted the secretion of SCF, TGF-β and IL-6. Conclusions: PEDF inhibits the increased endothelial permeability induced by irradiation and reverse the inhibitory effect of injured endothelial cells on hematopoietic stem cells and promote hematopoietic reconstruction.
... [4][5][6][7][8][9] Radiation and chemotherapy disrupt the BM perivascular niche, leading to regression and remodeling of ECs and adipogenesis of LepR 1 cells. [10][11][12][13][14][15] HSC engraftment and proliferation after transplantation are supported by the BM microenvironment, including the perivascular niche. 10,13,[16][17][18][19] Thus, identification of factors that can protect the niche from irradiation damage or promote niche regeneration is of clinical interest and may improve HSC transplantation efficacy. ...
Article
Hematopoietic stem cells (HSCs) reside in the bone marrow (BM) stem cell niche, which provides a vital source of HSC regulatory signals. Radiation and chemotherapy disrupt the HSC niche, including its sinusoidal vessels and perivascular cells, contributing to delayed hematopoietic recovery. Thus, identification of factors that can protect the HSC niche in an injury could offer a significant therapeutic opportunity to improve hematopoietic regeneration. Here we show a critical function for vascular endothelial growth factor C (VEGF-C) in maintaining the integrity of the BM perivascular niche and improving BM niche recovery after irradiation-induced injury. Both global and conditional deletion of Vegfc in endothelial or leptin receptor+ (LepR+) cells led to a disruption of the BM perivascular niche. Furthermore, deletion of Vegfc from the microenvironment delayed hematopoietic recovery after transplantation by decreasing endothelial proliferation and LepR+ cell regeneration. Exogenous administration of VEGF-C via adeno-associated viral vector improved hematopoietic recovery after irradiation by accelerating endothelial and LepR+ cell regeneration and by increasing the expression of hematopoietic regenerative factors. Our results suggest that preservation of the integrity of the perivascular niche via VEGF-C signalling may be exploited therapeutically to enhance hematopoietic regeneration.
... 26 Then a specific instruction was needed to elucidate the way of the BM being an OAR in this article. The NCRT plus surgery was considered a new setting that optimal PTV and RT techniques could improve for locally advanced EC. 1 , 7 , 27 However, the chemoradiotherapy might cause the impairment of BM microvasculature, 28 which would result in hematologic toxicities (HT). 29 Wang, et al. reported a technique that they designed in comparison with IMRT and VMAT could decrease the BM irradiation, namely TOMO. ...
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This study compares dosimetric parameters in these following 3 neoadjuvant chemoradiotherapy (NCRT) methods in treating locally advanced esophagus cancer: helical tomotherapy (TOMO), volumetric modulated arc therapy (VMAT), and intensity-modulated radiotherapy (IMRT). It is aimed to ascertain the efficient technique that kept high target coverage and availed the dose sparing of bone marrow (BM). This research collected data on 11 patients from October 2014 to June 2017 who received NCRT for pathologically confirmed esophageal cancer. The prescription doses to the planning target volume (PTV) were all given as 60 Gy (2 Gy per fraction, 5 days a week). Three physicists via Varian Eclipse Treatment Planning System and Accuray planning stations redesigned 5 radiotherapy plans (fixed 5-field IMRT, fixed 7-field IMRT, 2-arc VMAT, 3-arc VMAT, and TOMO) for each of the patients. At the end of the planning, we then appraised the dosimetric quality based on the PTV parameters and the doses to organs at risk (OARs). In the study VMAT reached the highest conformity index (CI; 2 arcs VMAT: 0.74 ± 0.10; 3 arcs VMAT: 0.78 ± 0.07; p< 0.05), and IMRT the lowest homogeneity index (HI; fivefields IMRT: 0.12 ± 0.03; sevenfields IMRT: 0.10 ± 0.02; p< 0.05). Besides, 7 fields IMRT (0.10 ± 0.02) achieved superior HI to that of 5 fields IMRT (0.12 ± 0.03, p< 0.01). TOMO (p< 0.05) and VMAT (p< 0.05) were both significantly superior to IMRT in terms of the dose to lung (V5, V10, V15, V20, and V30). These 5 radiation techniques were similar regarding the dose to heart (V5, V20, and V30), but IMRT (5 fields IMRT: 19.27 ± 5.33; 7 fields IMRT: 20.05 ± 4.19) significantly raised the dose to the V50 of the heart when compared to VMAT (2 arcs VMAT: 16.6 ± 5.68; 3 arcs VMAT: 15.04 ± 5.75; p< 0.05) and TOMO (15.05 ± 4.7, p< 0.05). VMAT reduced the dose to BM (V5, V10, V20, and V30) as compared to TOMO (p< 0.05) and IMRT (p< 0.05). The CI of VMAT was the supreme one in those of the techniques in this study, so was the HI of IMRT. VMAT also provided another advantage that it reduced the dose to the BM. TOMO ameliorated the dose sparing of the lung, but the dose that the BM absorbed from TOMO was of some concern about BM toxicity.
... All accidents, bone tumor resection and debridement of bone infections may cause complex fractures [1]. In such situation, the bone regeneration occurs to compromise the loss of bone tissue and to connect the broken bones [2]. ...
Article
Mechanical stress has been recognized as a key inducer of bone regeneration in bone damage, which is experimentally mimicked by distraction osteogenesis (DO), a bone-regenerative process induced by post-osteotomy distraction of the surrounding vascularized bone segments, and realized by new bone formation within the distraction gap. The mechanisms that underlie the DO-induced bone regeneration remain poorly understood and a role of macrophages in the process has been inadequately studied. Here, in a mouse model of DO, we showed significant increase in macrophages in the regeneration area. Moreover, in a loss-of-function approach by depleting inflammatory macrophages, the bone regeneration was compromised by assessment of histology and molecular biology. Thus, our study demonstrates the necessary participation of inflammatory macrophages in the process of DO-induced bone regeneration, and suggests that targeting inflammatory macrophages may help to improve clinical bone repair.
... Despite of osteogenic differentiation mediated primarily by MSCs, it is likely that a bunch of factors are involved in markers, such as BMPs, Runx2, VEGF, TGF-β, and insulin-like growth factor 46,47 . Besides these, many tissue types exist in the bone, including vascular endothelium and connective tissues and autonomic and sensory nerves, which contribute to forming a favorable milieu for bone formation 48,49 . BMPs belong to the TGF-β super-family, which are recognized as playing critical roles in regulating bone formation and proliferation 50,51 , as well as in angiogenesis 52,53 . ...
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Human amniotic mesenchymal stem cells (hAMSCs) are multiple potent progenitor cells (MPCs) that can differentiate into different lineages (osteogenic, chondrogenic, and adipogenic cells) and have a favorable capacity for angiogenesis. Schnurri-3 (Shn3) is a large zinc finger protein related to Drosophila Shn, which is a critical mediator of postnatal bone formation. Bone morphogenetic protein 9 (BMP9), one of the most potent osteogenic BMPs, can strongly upregulate various osteogenesis- and angiogenesis-related factors in MSCs. It remains unclear how Shn3 is involved in BMP9-induced osteogenic differentiation coupled with angiogenesis in hAMSCs. In this investigation, we conducted a comprehensive study to identify the effect of Shn3 on BMP9-induced osteogenic differentiation and angiogenesis in hAMSCs and analyze the responsible signaling pathway. The results from in vitro and in vivo experimentation show that Shn3 notably inhibits BMP9-induced early and late osteogenic differentiation of hAMSCs, expression of osteogenesis-related factors, and subcutaneous ectopic bone formation from hAMSCs in nude mice. Shn3 also inhibited BMP9-induced angiogenic differentiation, expression of angiogenesis-related factors, and subcutaneous vascular invasion in mice. Mechanistically, we found that Shn3 prominently inhibited the expression of BMP9 and activation of the BMP/Smad and BMP/MAPK signaling pathways. In addition, we further found activity on runt-related transcription factor 2 (Runx2), vascular endothelial growth factor (VEGF), and the target genes shared by BMP and Shn3 signaling pathways. Silencing Shn3 could dramatically enhance the expression of Runx2, which directly regulates the downstream target VEGF to couple osteogenic differentiation with angiogenesis. To summarize, our findings suggested that Shn3 significantly inhibited the BMP9-induced osteogenic differentiation and angiogenesis in hAMSCs. The effect of Shn3 was primarily seen through inhibition of the BMP/Smad signaling pathway and depressed expression of Runx2, which directly regulates VEGF, which couples BMP9-induced osteogenic differentiation with angiogenesis.