Akiva Mintz

Endothelial cells maintain neural stem cells quiescent in their niche

Niches are specialized microenvironments that regulate stem cells activity. The neural stem cell (NSC) niche defines a zone in which NSCs are retained and produce new cells of the nervous system throughout life. Understanding the signaling mechanisms by which the niche controls the NSC fate is crucial for the success of clinical applications. In a recent study, Sato and colleagues, by using state-of-the-art techniques, including sophisticated in vivo lineage-tracing technologies, provide evidence that endothelial amyloid precursor protein (APP) is an important component of the NSC niche. Strikingly, depletion of APP increased NSC proliferation in the subventricular zone, indicating that endothelial cells negatively regulate NSCs growth. The emerging knowledge from this research will be important for the treatment of several neurological diseases.

Endothelial Cells as Precursors for Osteoblasts in the Metastatic Prostate Cancer Bone

Prostate cancer cells metastasize to the bones, causing ectopic bone formation, which results in fractures and pain. The cellular mechanisms underlying new bone production are unknown. In a recent study, Lin and colleagues, by using state-of-the-art techniques, including prostate cancer mouse models in combination with sophisticated in vivo lineage-tracing technologies, revealed that endothelial cells form osteoblasts induced by prostate cancer metastasis in the bone. Strikingly, genetic deletion of osteorix protein from endothelial cells affected prostate cancer–induced osteogenesis in vivo. Deciphering the osteoblasts origin in the bone microenvironment may result in the development of promising new molecular targets for prostate cancer therapy.

Pericytes Make Spinal Cord Breathless after Injury

Traumatic spinal cord injury is a devastating condition that leads to significant neurological deficits and reduced quality of life. Therapeutic interventions after spinal cord lesions are designed to address multiple aspects of the secondary damage. However, the lack of detailed knowledge about the cellular and molecular changes that occur after spinal cord injury restricts the design of effective treatments. Li and colleagues using a rat model of spinal cord injury and in vivo microscopy reveal that pericytes play a key role in the regulation of capillary tone and blood flow in the spinal cord below the site of the lesion. Strikingly, inhibition of specific proteins expressed by pericytes after spinal cord injury diminished hypoxia and improved motor function and locomotion of the injured rats. This work highlights a novel central cellular population that might be pharmacologically targeted in patients with spinal cord trauma. The emerging knowledge from this research may provide new approaches for the treatment of spinal cord injury.

Role of pericytes in the retina

Diabetic retinopathy is a major severe ocular complication associated with the metabolic disorder of diabetes mellitus.1 The lack of a detailed knowledge about the cellular and molecular mechanisms involved in diabetic retinopathy restricts the design of effective treatments. Understanding the roles of retinal cells during this process is of utmost importance, since gaining control of specific cell populations may allow us to arrest or even induce reversion of diabetic retinopathy. Pericyte dropout or loss has been suggested to have great consequences on blood vessel remodeling, and possibly causes the first abnormalities of the diabetic eye which can be observed clinically in diabetic retinopathy.2 Nevertheless, a concreate evidence to support this concept is not available. Surprisingly, in a recent article in Nature Communications, Park and colleagues demonstrated that pericytes are not essential in the adult stable retinal blood vessels; and their selective depletion did not lead to a phenotype similar to diabetic retinopathy.3 The authors used a transgenic mouse model which can be used to specifically ablate PDGFRβexpressing pericytes (PDGFRβ-CreER/DTA mice). Several studies suggest that PDGFB released from vascular endothelial cells recruits PDGFRβ-expressing pericytes to facilitate vascular stabilization during blood vessel development.4 Nonetheless, whether this PDGFB/PDGFRβ signaling continues to be necessary for proper pericyte attachment to stable adult retinal vasculature was unknown. Park and colleagues used VE-Cadherin (Endothelial specific)-CreER/PDGFB floxed mice and intra-vitreal administration of PDGFRβ blocking antibody to show that PDGFB/ PDGFRβ signaling is not required for the maintenance of the interaction between pericytes and endothelial cells, and for the integrity of the blood-retinal-barrier in adults.3 In contrast, Park and colleagues demonstrated using state-of-the-art techniques, including deletion of several genes from endothelial cells, that PDGFB/PDGFRβ signaling is indispensable in the formation and maturation of bloodretinal-barrier at the postnatal stage through active recruitment of pericytes onto the growing retinal vessels.3 Additionally, the authors revealed that pericytes are important in the adult retina as regulators, as they control the expression of several genes (FOXO1, Ang2, and VEGFR2) to protect retinal vessels against injuries and stresses.3 Here, we discuss the findings from this work, and evaluate recent advances in our understanding of pericytes roles in the retina.

Macrophages Generate Pericytes in the Developing Brain

Pericytes are defined by their anatomical location encircling blood vessels walls with their long projections. The exact embryonic sources of cerebral pericytes remain poorly understood, especially because of their recently revealed diversity. Yamamoto et al. (Sci Rep 7(1):3855, 2017) using state-of-the-art techniques, including several transgenic mice models, reveal that a subpopulation of brain pericytes are derived from phagocytic macrophages during vascular development. This work highlights a new possible ancestor of brain pericytes. The emerging knowledge from this research may provide new approaches for the treatment of several neurodevelopmental disorders in the future.

Pericytes modulate myelination in the central nervous system

Multiple sclerosis is a highly prevalent chronic demyelinating disease of the central nervous system. Remyelination is the major therapeutic goal for this disorder. The lack of detailed knowledge about the cellular and molecular mechanisms involved in myelination restricts the design of effective treatments. A recent study by using [De La Fuente et al. (2017) Cell Reports, 20(8): 1755‐1764] by using state‐of‐the‐art techniques, including pericyte‐deficient mice in combination with induced demyelination, reveal that pericytes participate in central nervous system regeneration. Strikingly, pericytes presence is essential for oligodendrocyte progenitors differentiation and myelin formation during remyelination in the brain. The emerging knowledge from this research will be important for the treatment of multiple sclerosis.

Pericytes constrict blood vessels after myocardial ischemia

No-reflow phenomenon is defined as the reduced blood flow after myocardial ischemia. If prolonged it leads to profound damages in the myocardium. The lack of a detailed knowledge about the cells mediating no-reflow restricts the design of effective therapies. Recently, OFarrell et al. (2017) by using state-of-the-art technologies, including high-resolution confocal imaging in combination with myocardial ischemia/reperfusion mouse model, reveal that pericytes contribute to the no-reflow phenomenon post-ischemia in the heart. Strikingly, intravenous adenosine increased vascular diameter at pericyte site after cardiac ischemia. This study provides a novel therapeutic target to inhibit no-reflow phenomenon after myocardial ischemia.

Adipocytes role in the bone marrow niche: Adipocytes Stimulate Hematopoietic Regeneration After Myeloablation

Adipocyte infiltration in the bone marrow follows chemotherapy or irradiation. Previous studies indicate that bone marrow fat cells inhibit hematopoietic stem cell function. Recently, Zhou et al. (2017) using state‐of‐the‐art techniques, including sophisticated Cre/loxP technologies, confocal microscopy, in vivo lineage‐tracing, flow cytometry, and bone marrow transplantation, reveal that adipocytes promote hematopoietic recovery after irradiation. This study challenges the current view of adipocytes as negative regulators of the hematopoietic stem cells niche, and reopens the discussion about adipocytes roles in the bone marrow. Strikingly, genetic deletion of stem cell factor specifically from adipocytes leads to deficiency in hematopoietic stem cells, and reduces animal survival after myeloablation, The emerging knowledge from this research will be important for the treatment of multiple hematologic disorders.

Glioblastoma-activated pericytes support tumor growth via immunosuppression

Glioblastoma multiforme is the most common and aggressive primary brain tumor, with an extremely poor prognosis. The lack of detailed knowledge about the cellular and molecular mechanisms involved in glioblastoma development restricts the design of efficient therapies. A recent study using state‐of‐art technologies explores the role of pericytes in the glioblastoma microenvironment. Glioblastoma‐activated pericytes develop an immunosuppressive phenotype, reducing T‐cell activation through the induction of an anti‐inflammatory response. Strikingly, pericytes support glioblastoma growth in vitro and in vivo. Here, we describe succinctly the results and implications of the findings reported in pericytes and glioblastomas biology. The emerging knowledge from this study will be essential for the treatment of brain tumors.

Macrophage-derived GPNMB accelerates skin healing

Healing is a vital response important for the re‐establishment of the skin integrity following injury. Delayed or aberrant dermal wound healing leads to morbidity in patients. The development of therapies to improve dermal healing would be useful. Currently, the design of efficient treatments is stalled by the lack of detailed knowledge about the cellular and molecular mechanisms involved in wound healing. Recently, using state‐of‐the‐art technologies, it was revealed that macrophages signal via GPNMB to mesenchymal stem cells, accelerating skin healing. Strikingly, transplantation of macrophages expressing GPNMB improves skin healing in GPNMB‐mutant mice. Additionally, topical treatment with recombinant GPNMB restored mesenchymal stem cells recruitment and accelerated wound closure in the diabetic skin. From a drug development perspective, this GPNMB is a new candidate for skin healing.