Patrick O. Azevedo

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.

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 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.

Perivascular cell αv integrins as a target to treat skeletal muscle fibrosis

Fibrosis following injury leads to aberrant regeneration and incomplete functional recovery of skeletal muscle, but the lack of detailed knowledge about the cellular and molecular mechanisms involved hampers the design of effective treatments. Using state-of-the-art technologies, Murray et al. (2017) found that perivascular PDGFRβ-expressing cells generate fibrotic cells in the skeletal muscle. Strikingly, genetic deletion of αv integrins from perivascular PDGFRβ-expressing cells significantly inhibited skeletal muscle fibrosis without affecting muscle vascularization or regeneration. In addition, the authors showed that a small molecule inhibitor of αv integrins, CWHM 12, attenuates skeletal muscle fibrosis. From a drug-development perspective, this study identifies a new cellular and molecular target to treat skeletal muscle fibrosis.

Cross-talk between lung cancer and bones results in neutrophils that promote tumor progression

Lung cancer is the leading cause of cancer mortality around the world. The lack of detailed understanding of the cellular and molecular mechanisms participating in the lung tumor progression restrains the development of efficient treatments. Recently, by using state-of-the-art technologies, including in vivo sophisticated Cre/loxP technologies in combination with lung tumor models, it was revealed that osteoblasts activate neutrophils that promote tumor growth in the lung. Strikingly, genetic ablation of osteoblasts abolished lung tumor progression via interruption of SiglecFhigh–expressing neutrophils supply to the tumor microenvironment. Interestingly, SiglecFhigh neutrophil signature was associated with worse lung adenocarcinoma patients outcome. This study identifies novel cellular targets for lung cancer treatment. Here, we summarize and evaluate recent advances in our understanding of lung tumor microenvironment.