Meenakshi Rao

Gremlin 1 Identifies a Skeletal Stem Cell with Bone, Cartilage, and Reticular Stromal Potential

The stem cells that maintain and repair the postnatal skeleton remain undefined. One model suggests that perisinusoidal mesenchymal stem cells (MSCs) give rise to osteoblasts, chondrocytes, marrow stromal cells, and adipocytes, although the existence of these cells has not been proven through fate-mapping experiments. We demonstrate here that expression of the bone morphogenetic protein (BMP) antagonist gremlin 1 defines a population of osteochondroreticular (OCR) stem cells in the bone marrow. OCR stem cells self-renew and generate osteoblasts, chondrocytes, and reticular marrow stromal cells, but not adipocytes. OCR stem cells are concentrated within the metaphysis of long bones not in the perisinusoidal space and are needed for bone development, bone remodeling, and fracture repair. Grem1 expression also identifies intestinal reticular stem cells (iRSCs) that are cells of origin for the periepithelial intestinal mesenchymal sheath. Grem1 expression identifies distinct connective tissue stem cells in both the bone (OCR stem cells) and the intestine (iRSCs).

The bowel and beyond: the enteric nervous system in neurological disorders

The enteric nervous system (ENS) is large, complex and uniquely able to orchestrate gastrointestinal behaviour independently of the central nervous system (CNS). An intact ENS is essential for life and ENS dysfunction is often linked to digestive disorders. The part the ENS plays in neurological disorders, as a portal or participant, has also become increasingly evident. ENS structure and neurochemistry resemble that of the CNS, therefore pathogenic mechanisms that give rise to CNS disorders might also lead to ENS dysfunction, and nerves that interconnect the ENS and CNS can be conduits for disease spread. We review evidence for ENS dysfunction in the aetiopathogenesis of autism spectrum disorder, amyotrophic lateral sclerosis, transmissible spongiform encephalopathies, Parkinson disease and Alzheimer disease. Animal models suggest that common pathophysiological mechanisms account for the frequency of gastrointestinal comorbidity in these conditions. Moreover, the neurotropic pathogen, varicella zoster virus (VZV), unexpectedly establishes latency in enteric and other autonomic neurons that do not innervate skin. VZV reactivation in these neurons produces no rash and is therefore a clandestine cause of gastrointestinal disease, meningitis and strokes. The gut–brain alliance has raised consciousness as a contributor to health, but a gut–brain axis that contributes to disease merits equal attention.

Enteric glia express proteolipid protein 1 and are a transcriptionally unique population of glia in the mammalian nervous system

In the enteric nervous system (ENS), glia outnumber neurons by 4‐fold and form an extensive network throughout the gastrointestinal tract. Growing evidence for the essential role of enteric glia in bowel function makes it imperative to understand better their molecular marker expression and how they relate to glia in the rest of the nervous system. We analyzed expression of markers of astrocytes and oligodendrocytes in the ENS and found, unexpectedly, that proteolipid protein 1 (PLP1) is specifically expressed by glia in adult mouse intestine. PLP1 and S100β are the markers most widely expressed by enteric glia, while glial fibrillary acidic protein expression is more restricted. Marker expression in addition to cellular location and morphology distinguishes a specific subpopulation of intramuscular enteric glia, suggesting that a combinatorial code of molecular markers can be used to identify distinct subtypes. To assess the similarity between enteric and extraenteric glia, we performed RNA sequencing analysis on PLP1‐expressing cells in the mouse intestine and compared their gene expression pattern to that of other types of glia. This analysis shows that enteric glia are transcriptionally unique and distinct from other cell types in the nervous system. Enteric glia express many genes characteristic of the myelinating glia, Schwann cells and oligodendrocytes, although there is no evidence of myelination in the murine ENS. GLIA 2015;63:2040–2057

Neurogastroenterology: The dynamic cycle of life in the enteric nervous system

The stability of the neuronal circuits and cells of the enteric nervous system can no longer be taken for granted; new evidence suggests astounding rates of apoptosis and neurogenesis.

Perceptions of gender equality in work-life balance, salary, promotion, and harassment: Results of the NASPGHAN task force survey

Objectives: Gender equality in the workplace has not been described in pediatric gastroenterology. Methods: An electronic survey that explored perceptions of career parity, work–life balance, and workplace harassment was sent to all members of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. Reponses were anonymous. Results: Of the 303 respondents (21%), there was an even distribution across geographic region, age, and gender (54% men). Gender affected perception of salary and promotion; 46% of men but only 9% of women feel that “women earn the same as men” (P < 0.001). Similarly, 48% of men but only 12% of women feel that “women rise at the same rate as men” (P < 0.001). Both genders of academic practice respondents, compared with other practice models, perceived men were promoted more quickly than women (P = 0.008). Women had higher dissatisfaction with mentoring than men (29% vs 13%, P = 0.03). Significantly more men than women reported spouses with “flexible jobs” (35% vs 14%, P < 0.001). Having a spouse with “flexible job” or having children (preschool or school age), however, did not affect satisfaction with work–life balance for either gender. Overall, women are more likely to be dissatisfied with work–life balance than men (P = 0.046). Conclusions: Satisfaction with work–life balance is lower among women versus men pediatric gastroenterologists, but does not correlate with flexibility of spouses job or caring for young children. Gender-divergent perception of promotion, parity of compensation, and mentoring requires further investigation.

Bugs, Guts, and Glia: How Microbiota Influence Enteric Gliogenesis and Migration

Enteric glia are neural crest derivatives. Kabouridis et al. (2015) now show in adult animals that new glia arise within the ganglia of enteric plexuses and then migrate centripetally to colonize the mucosa. Remarkably, enteric microbiota regulate this critical migration.

Enteric nervous system development: what could possibly go wrong?

The gastrointestinal tract contains its own set of intrinsic neuroglial circuits — the enteric nervous system (ENS) — which detects and responds to diverse signals from the environment. Here, we address recent advances in the understanding of ENS development, including how neural-crest-derived progenitors migrate into and colonize the bowel, the formation of ganglionated plexuses and the molecular mechanisms of enteric neuronal and glial diversification. Modern lineage tracing and transcription-profiling technologies have produced observations that simultaneously challenge and affirm long-held beliefs about ENS development. We review many genetic and environmental factors that can alter ENS development and exert long-lasting effects on gastrointestinal function, and discuss how developmental defects in the ENS might account for some of the large burden of digestive disease.The gastrointestinal tract is innervated by the enteric nervous system (ENS), and disruption of ENS development can result in various gastrointestinal disorders. Here, Rao and Gershon review the complex processes involved in ENS development, including cell migration, proliferation and organization.

384 Enteric Glia Are a Transcriptionally Distinct and Heterogeneous Class of Glia in the Mammalian Nervous System

In the enteric nervous system (ENS), glia outnumber neurons by 4 to 6-fold and form an extensive network throughout the gastrointestinal tract. Enteric glia are essential for normal gastrointestinal function and play roles in regulating epithelial barrier integrity, epithelial cell proliferation and neuronal support. While glial subtypes can be clearly distinguished in the central and peripheral nervous systems (CNS and PNS), it remains unknown whether similar glial diversity exists in the ENS. Because of their morphology and expression of Glial Fibrillary Acidic Protein (GFAP), until recently, enteric glia were thought to resemble astrocytes. We tested the hypothesis that enteric glia instead constitute a unique and heterogeneous group of glial cells. To define the level of heterogeneity, we first analyzed expression of the markers S100β, Sox10, GFAP, and proteolipid protein 1 (PLP1) in the small and large intestine of adult mice. Sox10 and S100β are widely expressed by enteric glia throughout the intestine. GFAP expression, however, is more restricted. Marker expression in combination with cellular location reproducibly distinguished subpopulations of enteric glia, suggesting that functional subtypes are likely to exist. Unexpectedly, we found that PLP1 is widely expressed by enteric glia, although they do not myelinate axons. We then performed RNA sequencing analysis (RNA-Seq) on PLP1-expressing cells in the mouse intestine and compared their gene expression to that of other types of glia in the CNS and PNS. This showed that enteric glia are transcriptionally distinct from other glial classes, and share the greatest similarity to myelinating glia. The gene expression database generated by this study will facilitate future studies of glial function in gastrointestinal physiology.