Ana E. Paiva

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 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.

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.

The role of natural killer cells in the uterine microenvironment during pregnancy

Pregnancy is a choreographed physiological phenomenon that involves maternal-fetal cross-talk. Elucidating the cellular and molecular mechanisms involved in this communication will allow us to develop therapies for gestational complications. Little is known about the role of natural killer (NK) cells in the uterine microenvironment. In a recent study, Fu et al. (2017) used state-ofart technologies and showed that NK cells stimulate fetal growth via growth-promoting factors. Strikingly, transplantation of uterine NK cells from normal mice reversed the negative pregnancy outcome in NK cell-deficient transgenic mice, as well as in aged mice. This new knowledge provides insight into the role of NK cells in the uterine microenvironment during pregnancy. Approximately 20% of pregnancies result in embryonic death losses in mammals. Pregnancy is a complex physiological process influenced by multiple genetic, epigenetic, and microenvironmental factors, such as hormonal balance, immune tolerance, and angiogenesis. Fetal growth during development demands the expansion of cells, commonly followed by cellular specialization and the generation of distinct organs. Information on the control of this growth remains very limited. Effective regulation of fetal development is essential for successful mammalian reproduction. Disturbances in this process may lead to several gestational complications including infertility, fetal growth restriction, spontaneous abortion, and premature delivery. Survival of the embryo in the uterus is dependent on multiple cellular and molecular events that occur in this microenvironment. Hormones, cytokines, homeotic proteins, growth factors, and morphogens produced by a variety of cell types may influence pregnancy outcomes. The specific cells and the underlying mechanisms that directly contribute to the outcome of a pregnancy remain completely unknown. The lack of detailed knowledge about the cellular contributors that mediate pregnancy failures restricts the design of effective treatments. Understanding the regulation of fetal growth that occurs during pregnancy is a central question in reproduction research. The uterine microenvironment during pregnancy is highly complex and is replete with different cell populations, including activated immune cells. Most of the uterine immune cells identified during pregnancy are natural killer (NK) cells. These cells were classically named due to their capacity to eliminate target cells without previous priming in a “natural” manner. As an important component of innate lymphoid cells, NK cells are capable of perceiving and eradicating malignant cells and cells infected with intracellular pathogens, such as viruses, parasites, and bacteria. NK cells play essential roles in coordinating innate and adaptive immune responses by releasing a variety of molecules, including IFNγ, TGFβ, and IL10. The function of these cells in the uterus during normal pregnancy remains to be elucidated. In a recent article in Immunity, Fu et al. investigated the role of uterine NK cells during pregnancy. By using state-of-the-art techniques, the authors showed that NK cells induce fetal growth in the uterus. Fu and colleagues reported a NK cell subpopulation that expressed CD49a and Eomes produce growth-promoting factors such as pleiotrophin, osteoglycin, and osteopontin. The authors also showed using co-culture systems that a cross-talk between HLAG on fetal trophoblasts and KIR2DL4 on uterine NK cells is needed to promote the secretion of growth-promoting factors by NK cells. Additionally, uterine NK cells from patients who experienced recurrent spontaneous abortion significantly decreased the expression of growth-promoting factors. To examine whether insufficient secretion of growth-promoting factors from NK cells in the uterus affects fetal growth, Fu and colleagues analyzed fetal growth in mice with genetically ablated NK cells. These experiments revealed that absence of maternal NK cells influenced the pregnancy outcome, leading to defective fetal development. Interestingly, aging was characterized by the decrease in the number of uterine CD49a-expressing NK cells and in the expression of growth-promoting factors (Fig. 1). Strikingly, a transfer of uterine NK cells from normal mice reversed the pregnancy outcome in NK cell-deficient transgenic mouse models, as well as in aged mice. Notably, NK cells from mice that do not express the pleiotrophin, osteoglycin, and osteopontin growthpromoting factors were not able to reverse the impairment in fetal development. Here, we discuss these findings and evaluate the recent advances in our understanding of the biology of NK cells in the uterus.

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.