Luiza Lousado

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.

Hypothalamic Neurons Take Center Stage in the Neural Stem Cell Niche

Neural stem cells (NSCs) are a heterogeneous population of cells that generate new neurons in adult animals. Recently in Science, Paul etxa0al. (2017) show that hypothalamic neurons control activation of a subset of NSCs in response to feeding, providing insights into how physiological cues may influence stem cell activation.

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.

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.

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.

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.

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.

Pericytes in the Premetastatic Niche

The premetastatic niche formed by primary tumor-derived molecules contributes to fixation of cancer metastasis. The design of efficient therapies is limited by the current lack of knowledge about the details of cellular and molecular mechanisms involved in the premetastatic niche formation. Recently, the role of pericytes in the premetastatic niche formation and lung metastatic tropism was explored by using state-of-the-art techniques, including in vivo lineage-tracing and mice with pericyte-specific KLF4 deletion. Strikingly, genetic inactivation of KLF4 in pericytes inhibits pulmonary pericyte expansion and decreases metastasis in the lung. Here, we summarize and evaluate recent advances in the understanding of pericyte contribution to premetastatic niche formation. Cancer Res; 78(11); 2779-86. ©2018 AACR.