Pedro H.D.M. Prazeres

Pericytes are heterogeneous in their origin within the same tissue

Pericytes heterogeneity is based on their morphology, distribution, and markers. It is well known that pericytes from different organs may have distinct embryonic sources. Yamazaki et al. (2017) using several transgenic mouse model reveal by cell-lineage tracing that pericytes are even more heterogeneous than previously appreciated. This study shows that pericytes from within the same tissue may be heterogeneous in their origin. Remarkably, a subpopulation of embryonic dermal pericytes derives from the hematopoietic lineage, an unexpected source. Reconstructing the lineage of pericytes is central to understanding development, and also for the diagnosis and treatment of diseases in which pericytes play important roles.

Lung as a Niche for Hematopoietic Progenitors

Platelets are released from megakaryocytes. The bone marrow has been proposed to be the major site where this process occurs. Lefrançais et al. (2017) using state-of-the-art techniques including two-photon microscopy, in vivo lineage-tracing technologies, and sophisticated lung transplants reveal that the lung is also a primary site for platelet biogenesis. Strikingly, lung megakaryocytes can completely reconstitute platelet counts in the blood in mice with thrombocytopenia. This study also shows that hematopoietic progenitors, with capacity to repopulate the bone marrow after irradiation, are present in the lungs. This work brings a novel unexpected role for the lung as a niche for hematopoiesis. The emerging knowledge from this research may be important for the treatment of several disorders.

Identity of Gli1+ cells in the bone marrow

Bone marrow fibrosis is a critical component of primary myelofibrosis in which normal bone marrow tissue and blood-forming cells are gradually replaced with scar tissue. The specific cellular and molecular mechanisms that cause bone marrow fibrosis are not understood. A recent study using state-of-the-art techniques, including in vivo lineage tracing, provides evidence that Gli1+ cells are the cells responsible for fibrotic disease in the bone marrow. Strikingly, genetic depletion of Gli1+ cells rescues bone marrow failure and abolishes myelofibrosis. This work introduces a new central cellular target for bone marrow fibrosis. The knowledge that emerges from this research will be important for the treatment of several malignant and nonmalignant disorders.

Schwann cell precursors as a source for adrenal gland chromaffin cells

Schwann cells are cells defined by their intimate relationship with axons in the peripheral nervous system throughout development. Schwann cell precursors depict the earliest developmental stage of the Schwann cell lineage. Schwann cell precursors arise from migrating neural crest cells. During embryonic development, Schwann cell precursors migrate along peripheral neuronal axons to their final destinations. Compared to mature Schwann cells, Schwann cell precursors have an increased survival and migratory capacity. Although Schwann cell precursors were historically considered primed toward Schwann cell differentiation, as their name states; recent studies suggest that these cells may behave as progenitors of other cell types as well. Schwann cell precursors give rise to parasympathetic and enteric neurons, melanocytes, endoneural fibroblasts, and odontoblasts. As the Schwann cell precursors escort growing nerves to nearly every organ during development, it is possible that their role as progenitors was downplayed in some unstudied tissues. Thus, whether Schwann cell precursors can differentiate into other cell types remains elusive. The adrenal gland contains secretory neuroendocrine cells in its medullar region, which are named chromaffin cells due to their production of colored polymers of catecholamines after exposure to the oxidizing agent chromate. Morphologically, chromaffin cells resemble endocrine cells by their lack of neurites, and large storage vesicles, with chromaffin granules. These cells synthesize and store hormones, peptides, and small molecules, which are secreted into the blood circulation, playing crucial roles in numerous physiological conditions, that is, vascular perfusion. Despite the importance of chromaffin cells, few studies have been done to reveal their exact origin. Understanding the origin and the processes that drive the formation of chromaffin cells is a central question in developmental biology. Early developmental studies introduced the idea and the general consensus holds that both adrenal chromaffin cells and sympathetic neurons are derivatives of the same sympathoadrenal progenitor. Now, in a recent study in Science, Adameyko’s group challenge the current view about chromaffin cells’ origin by using state-of-the-art techniques, including sophisticated in vivo inducible genetic lineagetracing approaches, specific Schwann cell precursor depletion, and genetic denervation. Their data revealed that during development Schwann cell precursors are the ancestors of adrenal medullar chromaffin cells. The authors investigated the progeny of Schwann cell precursors by using Plp1CreERT2/R26R mice to track specifically Schwann cell precursor-generated cells. These experiments unveiled that approximately half of chromaffin cells are derived from nerveassociated Schwann cell precursors. Furthermore, Furlan and colleagues showed defective chromaffin cell production in the adrenal medulla in Sox10-CreERT2/R26R mice, in which Schwann cell precursor ablation was induced at E11.5, indicating the necessity of Schwann cell precursors for chromaffin cell formation. In addition, the authors analyzed denervated adrenal medulla in HB9-Cre/Isl2DTA mice. Strikingly, the denervation caused a reduction in the number of chromaffin cells, adding evidence that Schwann cell precursors, which are attached to the nerves, are essential for chromaffin cell generation. Moreover, this study examined mice deficient in a critical gene for chromaffin cell differentiation (Ascl1 knockout mice). Furlan and colleagues show that inhibiting chromaffin cell differentiation, leads to accumulation of Schwann cell precursors that fail to differentiate. Although it has long been known that Schwann cell precursors have the capacity to differentiate into mature Schwann cells, the findings by Furlan et al. suggest that Schwann cell precursors are equally crucial for adrenal gland formation outside of the nervous system. The impressive unexpected plasticity of Schwann cell precursors indicates that these cells possibly affect tissue regeneration more broadly that previously was thought. This remarkable capacity of Schwann cell precursors opens the door to hypothesis about their unexplored roles in other organs, and represents a promising tool and research direction in regenerative biology. Here, we discuss the findings from this work, and evaluate recent advances in our understanding of the adrenal medulla biology.

LepR+ cells dispute hegemony with Gli1+ cells in bone marrow fibrosis

ABSTRACT Bone marrow fibrosis is a reactive process, and a central pathological feature of primary myelofibrosis. Revealing the origin of fibroblastic cells in the bone marrow is crucial, as these cells are considered an ideal, and essential target for anti-fibrotic therapy. In 2 recent studies, Decker et al. (2017) and Schneider et al. (2017), by using state-of-the-art techniques including in vivo lineage-tracing, provide evidence that leptin receptor (LepR)-expressing and Gli1-expressing cells are responsible for fibrotic tissue deposition in the bone marrow. However, what is the relationship between these 2 bone marrow cell populations, and what are their relative contributions to bone marrow fibrosis remain unclear. From a drug development perspective, these works bring new cellular targets for bone marrow fibrosis.

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.

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.

Bismuth(III) complexes with 2-acetylpyridine- and 2-benzoylpyridine-derived hydrazones: Antimicrobial and cytotoxic activities and effects on the clonogenic survival of human solid tumor cells.

Complexes [Bi(2AcPh)Cl2]·0.5H2O (1), [Bi(2AcpClPh)Cl2] (2), [Bi(2AcpNO2Ph)Cl2] (3), [Bi(2AcpOHPh)Cl2]·2H2O (4), [Bi(H2BzPh)Cl3]·2H2O (5), [Bi(H2BzpClPh)Cl3] (6), [Bi(2BzpNO2Ph)Cl2]·2H2O (7) and [Bi(H2BzpOHPh)Cl3]·2H2O (8) were obtained with 2-acetylpyridine phenylhydrazone (H2AcPh), its -para-chloro-phenyl- (H2AcpClPh), -para-nitro-phenyl (H2AcpNO2Ph) and -para-hydroxy-phenyl (H2AcpOHPh) derivatives, as well as with the 2-benzoylpyridine phenylhydrazone analogues (H2BzPh, H2BzpClPh, H2BzpNO2Ph, H2BzpOHPh). Upon coordination to bismuth(III) antibacterial activity against Gram-positive and Gram-negative bacterial strains significantly improved except for complex (4). The cytotoxic effects of the compounds under study were evaluated on HL-60, Jurkat and THP-1 leukemia, and on MCF-7 and HCT-116 solid tumor cells, as well as on non-malignant Vero cells. In general, 2-acetylpyridine-derived hydrazones proved to be more potent and more selective as cytotoxic agents than the corresponding 2-benzoylpyridine-derived counterparts. Exposure of HCT-116 cells to H2AcpClPh, H2AcpNO2Ph and complex (3) led to 99% decrease of the clonogenic survival. The IC50 values of these compounds were three-fold smaller when cells were cultured in soft-agar (3D) than when cells were cultured in monolayer (2D), suggesting that they constitute interesting scaffolds, which should be considered in further studies aiming to develop new drug candidates for the treatment of colon cancer.

Neurogenesis in the postnatal cerebellum after injury

The cerebellum plays major role in motor coordination and learning. It contains half of the neurons in the brain. Thus, deciphering the mechanisms by which cerebellar neurons are generated is essential to understand the cerebellar functions and the pathologies associated with it. In a recent study, Wojcinski et al. (2017) by using in vivo Cre/loxP technologies reveal that Nestin‐expressing progenitors repopulated the external granular cell layer after injury. Depletion of postnatal external granular cell layer is not sufficient to induce motor behavior defects in adults, as the cerebellum recovers these neurons. Strikingly, Nestin‐expressing progenitors differentiate into granule cell precursors and mature granule neurons after ablation of perinatal external granular layer, either by irradiation or by genetic ablation. This work identified a novel role of Nestin‐expressing progenitors in the cerebellar microenvironment during development, and revealed that extracellular signals can convert specified progenitors into multipotent stem cells. Here, we discuss the findings from this study, and evaluate recent advances in our understanding of the cerebellar neurogenesis.

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.