Platelets Prime Hematopoietic-Vascular Niche to Drive Angiocrine-Mediated Liver Regeneration

A critical function for blood vessels is that they secrete paracrine factors necessary for development, homeostasis and repair of the rest of all organs. Among them, the liver is a highly vascular organ, and can undergo regeneration after injury. This liver regeneration process is governed by dynamic interplay between hepatocytes and non-parenchymal cells, liver sinusoidal endothelial cells (LSECs). However, how factors produced from LSECs triggered by injury remains to be defined. Following mouse in vivo liver injury model, activated platelets deploy stromal cell-derived factor 1 and vascular endothelial growth factor A to stimulate CXCR7+ LSECs, orchestrating hepatic regeneration. Upon injection of carbon tetrachloride, platelets and CD11b+VEGFR1+ myeloid cells were recruited to LSECs enabling to replenish liver mass. Liver regeneration was impaired in thrombopoietin-deficient (Thpo-/-) mice repressing platelet production. This impeded regeneration phenotype was recapitulated in mice with either conditional ablation of Cxcr7 in LSEC (Cxcr7iΔ/iΔ) or Vegfr1 in myeloid cell (Vegfr1lysM/lysM). These mice exhibited suppressed expression of hepatocyte growth factor and Wnt2, two crucial hepatocyte propagation factors. Administration of recombinant thrombopoietin restored the prohibited liver regeneration in the tested genetic models. These results suggest that platelets and myeloid cells activate the vascular niche to produce pro-regenerative endothelial paracrine factors. Modulating this “hematopoietic-vascular niche” might help to develop regenerative therapy strategy for hepatic disorders

Platelets Prime Hematopoietic-Vascular Niche to Drive Angiocrine-Mediated Liver Regeneration

A critical function for blood vessels is that they secrete paracrine factors necessary for development, homeostasis and repair of the rest of all organs. Among them, the liver is a highly vascular organ, and can undergo regeneration after injury. This liver regeneration process is governed by dynamic interplay between hepatocytes and non-parenchymal cells, liver sinusoidal endothelial cells (LSECs). However, how factors produced from LSECs triggered by injury remains to be defined. Following mouse in vivo liver injury model, activated platelets deploy stromal cell-derived factor 1 and vascular endothelial growth factor A to stimulate CXCR7+ LSECs, orchestrating hepatic regeneration. Upon injection of carbon tetrachloride, platelets and CD11b+VEGFR1+ myeloid cells were recruited to LSECs enabling to replenish liver mass. Liver regeneration was impaired in thrombopoietin-deficient (Thpo-/-) mice repressing platelet production. This impeded regeneration phenotype was recapitulated in mice with either conditional ablation of Cxcr7 in LSEC (Cxcr7iΔ/iΔ) or Vegfr1 in myeloid cell (Vegfr1lysM/lysM). These mice exhibited suppressed expression of hepatocyte growth factor and Wnt2, two crucial hepatocyte propagation factors. Administration of recombinant thrombopoietin restored the prohibited liver regeneration in the tested genetic models. These results suggest that platelets and myeloid cells activate the vascular niche to produce pro-regenerative endothelial paracrine factors. Modulating this “hematopoietic-vascular niche” might help to develop regenerative therapy strategy for hepatic disorders

Asynchronous abdomino-parasacral resection of a giant pelvic lipoma protruding to the left buttock

INTRODUCTION: Few reports detail adequate surgical management of giant pelvic tumors that traverse the sciatic foramen. PRESENTATION OF CASE: We present a case of a giant retroperitoneal pelvic lipoma that presented with a dumbbell shape on imaging, occupying the entire lesser pelvis and protruding to the gluteus through the sciatic foramen. Surgery was performed for en bloc resection of the tumor. DISCUSSION: A parasacral approach with the patient in the prone position was necessary to dissect the tumor in the buttock, manipulate around the sciatic foramen and preserve collateral blood flow for the gluteal muscle. An abdominal approach was also essential to ligate the internal iliac vessels involved in the tumor. Accordingly changings the position of the patient during the operation were required. Division of the sacrotuberous and sacrospinous ligaments and packing of the soft tumor into a plastic bag were useful to pass the buttock portion through the foramen without the tumor breaking off. CONCLUSION: The asynchronous abdomino-parasacral approach with several turnings of the patient's body and plastic bag packing of the tumor were advantageous to manage en bloc resection of the giant pelvic lipoma presented in this case study

Platelet-derived SDF-1 primes the pulmonary capillary vascular niche to drive lung alveolar regeneration

The lung alveoli regenerate after surgical removal of the left lobe by pneumonectomy (PNX). How this alveolar regrowth/regeneration is initiated remains unknown. We found that platelets trigger lung regeneration by supplying stromal-cell-derived factor-1 (SDF-1, also known as CXCL12). After PNX, activated platelets stimulate SDF-1 receptors CXCR4 and CXCR7 on pulmonary capillary endothelial cells (PCECs) to deploy the angiocrine membrane-type metalloproteinase MMP14, stimulating alveolar epithelial cell (AEC) expansion and neo-alveolarization. In mice lacking platelets or platelet Sdf1, PNX-induced alveologenesis was diminished. Reciprocally, infusion of Sdf1(+/+) but not Sdf1-deficient platelets rescued lung regeneration in platelet-depleted mice. Endothelial-specific ablation of Cxcr4 and Cxcr7 in adult mice similarly impeded lung regeneration. Notably, mice with endothelial-specific Mmp14 deletion exhibited impaired expansion of AECs but not PCECs after PNX, which was not rescued by platelet infusion. Therefore, platelets prime PCECs to initiate lung regeneration, extending beyond their haemostatic contribution. Therapeutic targeting of this haemo-vascular niche could enable regenerative therapy for lung diseases

Neurotrophins promote revascularization by local recruitment of TrkB(+) endothelial cells and systemic mobilization of hematopoietic progenitors

The neurotrophin brain-derived neurotrophic factor (BDNF) is required for the maintenance of cardiac vessel wall stability during embryonic development through direct angiogenic actions on endothelial cells expressing the tropomysin receptor kinase B (TrkB). However, the role of BDNF and a related neurotrophin ligand, neurotrophin-4 (NT-4), in the regulation of revascularization of the adult tissues is unknown. To study the potential angiogenic capacity of BDNF in mediating the neovascularization of ischemic and non-ischemic adult mouse tissues, we utilized a hindlimb ischemia and a subcutaneous Matrigel model. Recruitment of endothelial cells and promotion of channel formation within the Matrigel plug by BDNF and NT-4 was comparable to that induced by VEGF-A. The introduction of BDNF into non-ischemic ears or ischemic limbs induced neoangiogenesis, with a 2-fold increase in the capillary density. Remarkably, treatment with BDNF progressively increased blood flow in the ischemic limb over 21 days, similar to treatment with VEGF-A. The mechanism by which BDNF enhances capillary formation is mediated in part through local activation of the TrkB receptor and also by recruitment of Sca-1(+)CD11b(+) pro-angiogenic hematopoietic cells. BDNF induces a potent direct chemokinetic action on subsets of marrow-derived Sca-1(+) hematopoietic cells co-expressing TrkB. These studies suggest that local regional delivery of BDNF may provide a novel mechanism for inducing neoangiogenesis through both direct actions on local TrkB-expressing endothelial cells in skeletal muscle and recruitment of specific subsets of TrkB(+) bone marrow–derived hematopoietic cells to provide peri-endothelial support for the newly formed vessels

Combretastatin A4 phosphate induces rapid regression of tumor neovessels and growth through interference with vascular endothelial-cadherin signaling

The molecular and cellular pathways that support the maintenance and stability of tumor neovessels are not well defined. The efficacy of microtubule-disrupting agents, such as combretastatin A4 phosphate (CA4P), in inducing rapid regression of specific subsets of tumor neovessels has opened up new avenues of research to identify factors that support tumor neoangiogenesis. Herein, we show that CA4P selectively targeted endothelial cells, but not smooth muscle cells, and induced regression of unstable nascent tumor neovessels by rapidly disrupting the molecular engagement of the endothelial cell–specific junctional molecule vascular endothelial-cadherin (VE-cadherin) in vitro and in vivo in mice. CA4P increases endothelial cell permeability, while inhibiting endothelial cell migration and capillary tube formation predominantly through disruption of VE-cadherin/β-catenin/Akt signaling pathway, thereby leading to rapid vascular collapse and tumor necrosis. Remarkably, stabilization of VE-cadherin signaling in endothelial cells with adenovirus E4 gene or ensheathment with smooth muscle cells confers resistance to CA4P. CA4P synergizes with low and nontoxic doses of neutralizing mAbs to VE-cadherin by blocking assembly of neovessels, thereby inhibiting tumor growth. These data suggest that the microtubule-targeting agent CA4P selectively induces regression of unstable tumor neovessels, in part through disruption of VE-cadherin signaling. Combined treatment with anti–VE-cadherin agents in conjunction with microtubule-disrupting agents provides a novel synergistic strategy to selectively disrupt assembly and induce regression of nascent tumor neovessels, with minimal toxicity and without affecting normal stabilized vasculature

Molecular Signatures of Tissue-Specific Microvascular Endothelial Cell Heterogeneity in Organ Maintenance and Regeneration

SummaryMicrovascular endothelial cells (ECs) within different tissues are endowed with distinct but as yet unrecognized structural, phenotypic, and functional attributes. We devised EC purification, cultivation, profiling, and transplantation models that establish tissue-specific molecular libraries of ECs devoid of lymphatic ECs or parenchymal cells. These libraries identify attributes that confer ECs with their organotypic features. We show that clusters of transcription factors, angiocrine growth factors, adhesion molecules, and chemokines are expressed in unique combinations by ECs of each organ. Furthermore, ECs respond distinctly in tissue regeneration models, hepatectomy, and myeloablation. To test the data set, we developed a transplantation model that employs generic ECs differentiated from embryonic stem cells. Transplanted generic ECs engraft into regenerating tissues and acquire features of organotypic ECs. Collectively, we demonstrate the utility of informational databases of ECs toward uncovering the extravascular and intrinsic signals that define EC heterogeneity. These factors could be exploited therapeutically to engineer tissue-specific ECs for regeneration