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Adult neural crest stem-derived cells (NCSC) are of extraordinary high plasticity and promising candidates for use in regenerative medicine. Several locations such as skin, adipose tissue, dental pulp or bone marrow have been described in rodent, as sources of NCSC. However, very little information is available concerning their correspondence in human tissues, and more precisely for human bone marrow. The main objective of this study was therefore to characterize NCSC from adult human bone marrow. In this purpose, we compared human bone marrow stromal cells to human adipose tissue and dermis, already described for containing NCSC. We performed comparative analyses in terms of gene and protein expression as well as functional characterizations. It appeared that human bone marrow, similarly to adipose tissue and dermis, contains NESTIN+ / SOX9+ / TWIST+ / SLUG+ / P75NTR+ / BRN3A+/ MSI1+/ SNAIL1+ cells and were able to differentiate into melanocytes, Schwann cells and neurons. Moreover, when injected into chicken embryos, all those cells were able to migrate and follow endogenous neural crest migration pathways. Altogether, the phenotypic characterization and migration abilities strongly suggest the presence of neural crest-derived cells in human adult bone marrow.

The neuroepithelial stem cell protein, or Nestin, is a cytoskeletal intermediate filament initially characterized in neural stem cells. However, current extensive evidence obtained in in vivo models and humans shows presence of Nestin + cells with progenitor and/or regulatory functions in a number of additional tissues, remarkably bone marrow. This review presents the current knowledge on the role of Nestin in essential stem cell functions, including self-renewal/proliferation, differentiation and migration, in the context of the cytoskeleton. We further discuss the available in vivo models for the study of Nestin + cells and their progeny, their function and elusive nature in nervous system and bone marrow, and their potential mechanistic role and promising therapeutic value in preclinical models of disease. Future improved in vivo models and detection methods will allow to determine the true essence of Nestin + cells and confirm their potential application as therapeutic target in a range of diseases.

Abnormal cancer antioxidant capacity is considered as a potential mechanism of tumor malignancy. Modulation of oxidative stress status is emerging as an anti-cancer treatment. Our previous studies have found that Nestin-knockdown cells were more sensitive to oxidative stress in non-small cell lung cancer (NSCLC). However, the molecular mechanism by which Nestin protects cells from oxidative damage remains unclear. Here, we identify a feedback loop between Nestin and Nrf2 maintaining the redox homeostasis. Mechanistically, the ESGE motif of Nestin interacts with the Kelch domain of Keap1 and competes with Nrf2 for Keap1 binding, leading to Nrf2 escaping from Keap1-mediated degradation, subsequently promoting antioxidant enzyme generation. Interestingly, we also map that the antioxidant response elements (AREs) in the Nestin promoter are responsible for its induction via Nrf2. Taken together, our results indicate that the Nestin–Keap1–Nrf2 axis regulates cellular redox homeostasis and confers oxidative stress resistance in NSCLC. Loss of Nestin sensitizes non-small cell lung carcinoma (NSCLC) to oxidative stress. Here, the authors report a feedback loop between Nestin and Nrf2 wherein Nestin competes with Nrf2 for Keap1 binding, preventing Nrf2 degradation, and show the Nestin–Keap1–Nrf2 axis to regulate redox homeostasis in NSCLC.

According to current dogma, there is little or no ongoing neurogenesis in the fully developed adult enteric nervous system. This lack of neurogenesis leaves unanswered the question of how enteric neuronal populations are maintained in adult guts, given previous reports of ongoing neuronal death. Here, we confirm that despite ongoing neuronal cell loss because of apoptosis in the myenteric ganglia of the adult small intestine, total myenteric neuronal numbers remain constant. This observed neuronal homeostasis is maintained by new neurons formed in vivo from dividing precursor cells that are located within myenteric ganglia and express both Nestin and p75NTR, but not the pan-glial marker Sox10. Mutation of the phosphatase and tensin homolog gene in this pool of adult precursors leads to an increase in enteric neuronal number, resulting in ganglioneuromatosis, modeling the corresponding disorder in humans. Taken together, our results show significant turnover and neurogenesis of adult enteric neurons and provide a paradigm for understanding the enteric nervous system in health and disease.

Arterioles and sinusoids of the bone marrow (BM) are accompanied by stromal cells that express nerve/glial antigen 2 (NG2) and leptin receptor (LepR), and constitute specialized niches that regulate quiescence and proliferation of haematopoietic stem cells (HSCs). However, how niche cells differentially regulate HSC functions remains unknown. Here, we show that the effects of cytokines regulating HSC functions are dependent on the producing cell sources. Deletion of chemokine C-X-C motif ligand 12 (Cxcl12) or stem cell factor (Scf) from all perivascular cells marked by nestin-GFP dramatically depleted BM HSCs. Selective Cxcl12 deletion from arteriolar NG2 + cells, but not from sinusoidal LepR + cells, caused HSC reductions and altered HSC localization in BM. By contrast, deletion of Scf in LepR + cells, but not NG2 + cells, led to reductions in BM HSC numbers. These results uncover distinct contributions of cytokines derived from perivascular cells in separate vascular niches to HSC maintenance. Asada  et al.  examine differential effects of CXCL12 and SCF expression by perivascular bone marrow niche cells, such as arteriolar NG2 + vascular smooth muscle cells and sinusoidal LepR + cells, on haematopoietic stem cell maintenance and mobilization.

Microglia are resident immune cells that play critical roles in maintaining the normal physiology of the central nervous system (CNS). Remarkably, microglia have an intrinsic capacity to repopulate themselves after acute ablation. However, the underlying mechanisms that drive such restoration remain elusive. Here, we characterized microglial repopulation both spatially and temporally following removal via treatment with the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX5622. We show that microglia were replenished via self-renewal, with no contribution from nonmicroglial lineages, including Nestin+ progenitors and the circulating myeloid population. Interestingly, spatial analyses with dual-color labeling revealed that newborn microglia recolonized the parenchyma by forming distinctive clusters that maintained stable territorial boundaries over time, indicating the proximal expansive nature of adult microgliogenesis and the stability of microglia tiling. Temporal transcriptome profiling at different repopulation stages revealed that adult newborn microglia gradually regain steady-state maturity from an immature state that is reminiscent of the neonatal stage and follow a series of maturation programs, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, interferon immune activation, and apoptosis. Importantly, we show that the restoration of microglial homeostatic density requires NF-κB signaling as well as apoptotic egress of excessive cells. In summary, our study reports key events that take place from microgliogenesis to homeostasis reestablishment.

The establishment of cell identity during embryonic development involves the activation of specific gene expression programmes and is underpinned by epigenetic factors including DNA methylation and histone post-translational modifications. G-quadruplexes are four-stranded DNA secondary structures (G4s) that have been implicated in transcriptional regulation and cancer. Here, we show that G4s are key genomic structural features linked to cellular differentiation. We find that G4s are highly abundant in human embryonic stem cells and are lost during lineage specification. G4s are prevalent in enhancers and promoters. G4s that are found in common between embryonic and downstream lineages are tightly linked to transcriptional stabilisation of genes involved in essential cellular functions as well as transitions in the histone post-translational modification landscape. Furthermore, the application of small molecules that stabilise G4s causes a delay in stem cell differentiation, keeping cells in a more pluripotent-like state. Collectively, our data highlight G4s as important epigenetic features that are coupled to stem cell pluripotency and differentiation. Whether G-quadruplexes (G4s) regulate stem cell self-renewal and fate determination during embryonic development is not well understood. Here, the authors reveal that the embryonic stem cell state is defined by very high G4 abundance. G4s are progressively lost during differentiation as cells transit to lower lineage potential while artificial G4 stabilisation leads to delayed differentiation.

Supporting cells of the ovary, termed granulosa cells, are essential for ovarian differentiation and oogenesis by providing a nurturing environment for oocyte maintenance and maturation. Granulosa cells are specified in the fetal and perinatal ovary, and sufficient numbers of granulosa cells are critical for the establishment of follicles and the oocyte reserve. Identifying the cellular source from which granulosa cells and their progenitors are derived is an integral part of efforts to understand basic ovarian biology and the etiology of female infertility. In particular, the contribution of mesenchymal cells, especially perivascular cells, to ovarian development is poorly understood but is likely to be a source of new information regarding ovarian function. Here we have identified a cell population in the fetal ovary, which is a Nestin-expressing perivascular cell type. Using lineage tracing and ex vivo organ culture methods, we determined that perivascular cells are multipotent progenitors that contribute to granulosa, thecal, and pericyte cell lineages in the ovary. Maintenance of these progenitors is dependent on ovarian vasculature, likely reliant on endothelial–mesenchymal Notch signaling interactions. Depletion of Nestin⁺ progenitors resulted in a disruption of granulosa cell specification and in an increased number of germ cell cysts that fail to break down, leading to polyovular ovarian follicles. These findings highlight a cell population in the ovary and uncover a key role for vasculature in ovarian differentiation, which may lead to insights into the origins of female gonad dysgenesis and infertility.

Deer antlers are extraordinary mammalian organs that can fully regenerate annually. Antler renewal is a stem cell-based epimorphic process and antler stem (AS) cells can initiate de novo generation of antlers in postnatal mammals. However, although being called stem cells, the AS cells have not been characterized at molecular level based on the stem cell criteria. Comprehensive characterization of the AS cells would undoubtedly help to decipher the mechanism underlying the full regeneration of deer antlers, the only case of stem cell-based epimorphic regeneration in mammals. In the present study, three types of AS cells (antlerogenic periosteal cells APCs, for initial pedicle and first antler formation; pedicle periosteal cells PPC, for annual antler regeneration; and reserve mesenchyme cells RMCs, for rapid antler growth), were isolated for comprehensive molecular characterization. A horn-growth-related gene, RXFP2, was found to be expressed only in AS cells lineages but not in the facial periosteal cells (FPCs, locates geographically in the vicinity of the APCs or PPCs), suggesting the RXFP2 might be a specific marker for the AS cell lineage in deer. Our results demonstrated that AS cells expressed classic MSC markers including surface markers CD73, CD90, CD105 and Stro-1. They also expressed some of the markers including Tert, Nestin, S100A4, nucleostemin and C-Myc, suggesting that they have some attributes of the ESCs. Microinjection of male APC into deer blastocysts resulted in one female foetus (110 days gestation) recovered with obvious pedicle primordia with both male and female genotype detected in the ovary. In conclusion, the AS cells should be defined as MSCs but with partial attributes of ESCs.

Bone marrow endothelial cells (BMECs) form a network of blood vessels that regulate both leukocyte trafficking and haematopoietic stem and progenitor cell (HSPC) maintenance. However, it is not clear how BMECs balance these dual roles, and whether these events occur at the same vascular site. We found that mammalian bone marrow stem cell maintenance and leukocyte trafficking are regulated by distinct blood vessel types with different permeability properties. Less permeable arterial blood vessels maintain haematopoietic stem cells in a low reactive oxygen species (ROS) state, whereas the more permeable sinusoids promote HSPC activation and are the exclusive site for immature and mature leukocyte trafficking to and from the bone marrow. A functional consequence of high permeability of blood vessels is that exposure to blood plasma increases bone marrow HSPC ROS levels, augmenting their migration and differentiation, while compromising their long-term repopulation and survival. These findings may have relevance for clinical haematopoietic stem cell transplantation and mobilization protocols. Bone marrow endothelial cells have dual roles in the regulation of haematopoietic stem cell maintenance and in the trafficking of blood cells between the bone marrow and the blood circulatory system; this study shows that these different functions are regulated by distinct types of endothelial blood vessels with different permeability properties, affecting the metabolic state of their neighbouring stem cells. Bone marrow blood vessel specialization Endothelial cells of the bone marrow modulate both haematopoietic stem cell (HSC) maintenance and the trafficking of blood cells out of the bone marrow. Tsvee Lapidot and colleagues find that these two aspects are controlled by two distinct types of blood vessels in the bone marrow, with different permeability properties and reactive oxygen species (ROS) levels. Less permeable arteries surrounded by pericytes maintain HSCs in a low reactive oxygen species (ROS) state, whereas the more permeable smaller sinusoids promote HSC activation and allow trafficking of immature and mature leukocytes. The authors also show that in conditions that allow for expansion of HSCs, endothelial integrity is increased, with fewer blood cells moving in and out. Disruption of the endothelial barrier has the reverse effects. Elsewhere in this issue ( page 380 ), Anjali Kusumbe et al . demonstrate that Notch signalling in endothelial cells of bone marrow induces change in the capillaries and mesenchymal stem cells of the environment to support HSC amplification.