Liver-derived plasminogen mediates muscle stem cell expansion during caloric restriction through the plasminogen receptor Plg-R.

An intriguing effect of short-term caloric restriction (CR) is the expansion of certain stem cell populations, including muscle stem cells (satellite cells), which facilitate an accelerated regenerative program after injury. Here, we utilized the MetRS (MetRS) transgenic mouse to identify liver-secreted plasminogen as a candidate for regulating satellite cell expansion during short-term CR. Knockdown of circulating plasminogen prevents satellite cell expansion during short-term CR.

Plasminogen deficiency suppresses pancreatic ductal adenocarcinoma disease progression.

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal metastatic disease associated with robust activation of the coagulation and fibrinolytic systems. However, the potential contribution of the primary fibrinolytic protease plasminogen to PDAC disease progression has remained largely undefined. Mice bearing C57Bl/6-derived KPC (KRas , TRP53 ) tumors displayed evidence of plasmin activity in the form of high plasmin-antiplasmin complexes and high plasmin generation potential relative to mice without tumors.

Overexpression of Plg-R protects against adipose dysfunction and dysregulation of glucose homeostasis in diet-induced obese mice.

The plasminogen receptor, Plg-R is a unique cell surface receptor that is broadly expressed in cells and tissues throughout the body. Plg-R localizes plasminogen on cell surfaces and promotes its activation to the broad-spectrum serine protease, plasmin. In this study, we show that overexpression of Plg-R protects mice from high fat diet (HFD)-induced adipose and metabolic dysfunction.

Plg-R Expression in Human Breast Cancer Tissues.

The plasminogen activation system regulates the activity of the serine protease, plasmin. The role of plasminogen receptors in cancer progression is being increasingly appreciated as key players in modulation of the tumor microenvironment. The interaction of plasminogen with cells to promote plasminogen activation requires the presence of proteins exposing C-terminal lysines on the cell surface.

The plasminogen receptor Plg-R regulates adipose function and metabolic homeostasis.

Background: Plg-R , a unique transmembrane plasminogen receptor, enhances the activation of plasminogen to plasmin, and localizes the proteolytic activity of plasmin on the cell surface.

Objectives: We investigated the role of Plg-R in adipose function, metabolic homeostasis, and obesity.

Methods: We used adipose tissue (AT) sections from bariatric surgery patients and from high fat diet (HFD)-induced obese mice together with immunofluorescence and real-time polymerase chain reaction to study adipose expression of Plg-R .

Plasminogen Receptors and Fibrinolysis.

The ability of cells to promote plasminogen activation on their surfaces is now well recognized, and several distinct cell surface proteins have been demonstrated to function as plasminogen receptors. Here, we review studies demonstrating that plasminogen bound to cells, in addition to plasminogen directly bound to fibrin, plays a major role in regulating fibrin surveillance. We focus on the ability of specific plasminogen receptors on eukaryotic cells to promote fibrinolysis in the in vivo setting by reviewing data obtained predominantly in murine models.

The plasminogen receptor, Plg-R, plays a role in inflammation and fibrinolysis during cutaneous wound healing in mice.

Wound healing is a complex physiologic process that proceeds in overlapping, sequential steps. Plasminogen promotes fibrinolysis and potentiates the inflammatory response during wound healing. We have tested the hypothesis that the novel plasminogen receptor, Plg-R, regulates key steps in wound healing.

Exposure of plasminogen and a novel plasminogen receptor, Plg-RKT, on activated human and murine platelets.

Plasminogen activation rates are enhanced by cell surface binding. We previously demonstrated that exogenous plasminogen binds to phosphatidylserine-exposing and spread platelets. Platelets contain plasminogen in their α-granules, but secretion of plasminogen from platelets has not been studied.

Functions of the plasminogen receptor Plg-R.

Plg-R is a structurally unique transmembrane plasminogen receptor with both N- and C-terminal domains exposed on the extracellular face of the cell. Its C-terminal lysine functions to tether plasminogen to cell surfaces. Overexpression of Plg-R increases cell surface plasminogen binding capacity while genetic deletion of Plg-R decreases plasminogen binding.

Neuroendocrine Targeting of Tissue Plasminogen Activator (t-PA).

t-PA has a widespread neuroendocrine distribution including prominent expression in chromaffin cells of the sympathoadrenal system. Chromaffin cell t-PA is sorted into catecholamine storage vesicles and co-released with catecholamines in response to sympathoadrenal activation, suggesting that catecholamine storage vesicles may serve as a reservoir for the rapid release of t-PA. Chromogranin A (CgA), a major core protein in secretory vesicles throughout the neuroendocrine system, may play a crucial role in targeting proteins into the regulated secretory pathway, by forming aggregated "granin" complexes to which other proteins destined for the regulated secretory vesicle bind and become separated from constitutively secreted proteins in the trans-Golgi network (TGN).

Plasminogen and the Plasminogen Receptor, Plg-R, Regulate Macrophage Phenotypic, and Functional Changes.

Inflammation resolution is an active process that functions to restore tissue homeostasis. Clearance of apoptotic leukocytes by efferocytosis at inflammatory sites plays an important role in inflammation resolution and induces remarkable macrophage phenotypic and functional changes. Here, we investigated the effects of deletion of either plasminogen (Plg) or the Plg receptor, Plg-R, on the resolution of inflammation.

Differential expression of Plg-R and its effects on migration of proinflammatory monocyte and macrophage subsets.

Membrane-bound plasmin is used by immune cells to degrade extracellular matrices, which facilitates migration. The plasminogen receptor Plg-R is expressed by immune cells, including monocytes and macrophages. Among monocytes and macrophages, distinct subsets can be distinguished based on cell surface markers and pathophysiological function.

The plasminogen receptor Plg-R is essential for mammary lobuloalveolar development and lactation.

Unlabelled: Essentials Plg-R female mice give birth, but no offspring of Plg-R female mice survive to weaning. Causal mechanisms of potential lactational failure in Plg-R mice are unknown. Plg-R regulates extracellular matrix remodeling, cell proliferation, apoptosis, fibrin surveillance.

tPA and anger management for macrophages.

In this issue of , Mantuano et al in the Gonias laboratory elucidate a novel, protease-independent signaling pathway by which tissue plasminogen activator (tPA) negatively regulates the innate immune response of macrophages and neutralizes lipopolysaccharide (LPS) toxicity in vivo.

Astrocytes regulate the balance between plasminogen activation and plasmin clearance via cell-surface actin.

Plasminogen activation is involved in many processes within the central nervous system, including synaptic plasticity, neuroinflammation and neurodegeneration. However, the mechanisms that regulate plasminogen activation in the brain still remain unknown. Here we demonstrate that astrocytes participate in this regulation by two mechanisms.

Deficiency of plasminogen receptor, Plg-R , causes defects in plasminogen binding and inflammatory macrophage recruitment in vivo.

Unlabelled: Essentials Plg-R is a novel integral membrane plasminogen receptor. The functions of Plg-R in vivo are not known. Plg-R is a key player in macrophage recruitment in the inflammatory response in vivo.

Angry macrophages patrol for fibrin.

In this issue of Blood, Motley et al have identified a novel and unexpected mechanism for clearance of extravascular fibrin that is accomplished by a specific proinflammatory macrophage population and is dependent upon active plasmin, yet independent of known fibrinogen receptors.

Setting the table for macrophages.

In this issue of Blood, Das et al assign a very novel and unanticipated function to plasminogen by showing that it is an enhancer of the phagocytic function of macrophages.

Effect of combined treadmill training and magnetic stimulation on spasticity and gait impairments after cervical spinal cord injury.

Spasticity and gait impairments are two common disabilities after cervical spinal cord injury (C-SCI). In this study, we tested the therapeutic effects of early treadmill locomotor training (Tm) initiated at postoperative (PO) day 8 and continued for 6 weeks with injury site transcranial magnetic stimulation (TMSsc) on spasticity and gait impairments after low C6/7 moderate contusion C-SCI in a rat model. The combined treatment group (Tm+TMSsc) showed the most robust decreases in velocity-dependent ankle torques and triceps surae electromyography burst amplitudes that were time locked to the initial phase of lengthening, as well as the most improvement in limb coordination quantitated using three-dimensional kinematics and CatWalk gait analyses, compared to the control or single-treatment groups.

New insights into the role of Plg-RKT in macrophage recruitment.

Plasminogen (PLG) is the zymogen of plasmin, the major enzyme that degrades fibrin clots. In addition to its binding and activation on fibrin clots, PLG also specifically interacts with cell surfaces where it is more efficiently activated by PLG activators, compared with the reaction in solution. This results in association of the broad-spectrum proteolytic activity of plasmin with cell surfaces that functions to promote cell migration.

Peptidergic regulation of plasminogen activator inhibitor-1 gene expression in vivo.

Background: The mechanisms by which PAI-1 biosynthesis is altered during stress have not been fully elucidated. Studies suggest a major role for neuro-peptidergic modulation of the stress response by PACAP (pituitary adenylate cyclase-activating polypeptide), a member of the VIP/secretin/glucagon family.

Objective: We tested the hypothesis that PACAP regulates PAI-1 biosynthesis during stress in vivo.

Plasminogen receptors: the first quarter century.

The interaction of plasminogen with cell surfaces results in promotion of plasmin formation and retention on the cell surface. This results in arming cell surfaces with the broad-spectrum proteolytic activity of plasmin. Over the past quarter century, key functional consequences of the association of plasmin with the cell surface have been elucidated.

Effects of acute intrathecal baclofen in an animal model of TBI-induced spasticity, cognitive, and balance disabilities.

Spasticity is a major health problem for patients with traumatic brain injury (TBI). In addition to spasticity, TBI patients exhibit enduring cognitive, balance, and other motor impairments. Although the use of antispastic medications, particularly ITB, can decrease the severity of TBI-induced spasticity, current guidelines preclude the use of ITB during the first year after TBI.