Bone Marrow Stem Cells Derived from Nerves Have Neurogenic Properties and Potential Utility for Regenerative Therapy.

Neurons and glia of the peripheral nervous system are derived from progenitor cell populations, originating from embryonic neural crest. The neural crest and vasculature are intimately associated during embryonic development and in the mature central nervous system, in which they form a neurovascular unit comprised of neurons, glia, pericytes, and vascular endothelial cells that play important roles in health and disease. Our group and others have previously reported that postnatal populations of stem cells originating from glia or Schwann cells possess neural stem cell qualities, including rapid proliferation and differentiation into mature glia and neurons. Bone marrow receives sensory and sympathetic innervation from the peripheral nervous system and is known to contain myelinating and unmyelinating Schwann cells. Herein, we describe a population of neural crest-derived Schwann cells residing in a neurovascular niche of bone marrow in association with nerve fibers. These Schwann cells can be isolated and expanded. They demonstrate plasticity in vitro, generating neural stem cells that exhibit neurogenic potential and form neural networks within the enteric nervous system in vivo following transplantation to the intestine. These cells represent a novel source of autologous neural stem cells for the treatment of neurointestinal disorders.

A pilot study characterizing longitudinal changes in fecal microbiota of patients with Hirschsprung-associated enterocolitis.

PURPOSE: Hirschsprung disease is a neurointestinal disease that occurs due to failure of enteric neural crest-derived cells to complete their rostrocaudal migration along the gut mesenchyme, resulting in aganglionosis along variable lengths of the distal bowel. Despite the effective surgery that removes the aganglionic segment, children with Hirschsprung disease remain at high risk for developing a potentially life-threatening enterocolitis (Hirschsprung-associated enterocolitis). Although the etiology of this enterocolitis remains poorly understood, several recent studies in both mouse models and in human subjects suggest potential involvement of gastrointestinal microbiota in the underlying pathogenesis of Hirschsprung-associated enterocolitis. METHODS: We present the first study to exploit the Illumina MiSeq next-generation sequencing platform within a longitudinal framework focused on microbiomes of Hirschsprung-associated enterocolitis in five patients. We analyzed bacterial communities from fecal samples collected at different timepoints starting from active enterocolitis and progressing into remission. RESULTS: We observed compositional differences between patients largely attributable to variability in age at the time of sample collection. Remission samples across patients exhibited compositional similarity, including enrichment of Blautia, while active enterocolitis samples showed substantial variability in composition. CONCLUSIONS: Overall, our findings provide continued support for the role of GI microbiota in the pathogenesis of Hirschsprung-associated enterocolitis.

Is the Power Threshold of 0.8 Applicable to Surgical Science?-Empowering the Underpowered Study.

BACKGROUND: Many articles in the surgical literature were faulted for committing type 2 error, or concluding no difference when the study was "underpowered". However, it is unknown if the current power standard of 0.8 is reasonable in surgical science. METHODS: PubMed was searched for abstracts published in Surgery, JAMA Surgery, and Annals of Surgery and from January 1, 2012 to December 31, 2016, with Medical Subject Heading terms of randomized controlled trial (RCT) or observational study (OBS) and limited to humans were included (n = 403). Articles were excluded if all reported findings were statistically significant (n = 193), or if presented data were insufficient to calculate power (n = 141). RESULTS: A total of 69 manuscripts (59 RCTs and 10 OBSs) were assessed. Overall, the median power was 0.16 (interquartile range [IQR] 0.08-0.32). The median power was 0.16 for RCTs (IQR 0.08-0.32) and 0.14 for OBSs (IQR 0.09-0.22). Only 4 studies (5.8%) reached or exceeded the current 0.8 standard. Two-thirds of our study sample had an a priori power calculation (n = 41). CONCLUSIONS: High-impact surgical science was routinely unable to reach the arbitrary power standard of 0.8. The academic surgical community should reconsider the power threshold as it applies to surgical investigations. We contend that the blueprint for the redesign should include benchmarking the power of articles on a gradient scale, instead of aiming for an unreasonable threshold.

Nature versus nurture: the impact of nativity and site of treatment on survival for gastric cancer.

BACKGROUND: The prognosis of gastric cancer patients is better in Asia than in the West. Genetic, environmental, and treatment factors have all been implicated. We sought to explore the extent to which the place of birth and the place of treatment influences survival outcomes in Korean and US patients with localized gastric cancer. METHODS: Patients with localized gastric adenocarcinoma undergoing potentially curative gastrectomy from 1989 to 2010 were identified from the SEER registry and two single institution databases from the US and Korea. Patients were categorized into three groups: Koreans born/treated in Korea (KK), Koreans born in Korea/treated in the US (KUS), and White Americans born/treated in the US (W), and disease-specific survival rates compared. RESULTS: We identified 16,622 patients: 3,984 (24.0%) KK, 1,046 (6.3%) KUS, and 11,592 (69.7%) W patients. KK patients had longer unadjusted median (not reached) and 5-year disease-specific survival (81.6%) rates than KUS (87 months, 55.9%) and W (35 months, 39.2%; p < 0.001 for all comparisons) patients. This finding persisted on subset analyses of patients with stage IA tumors, without cardia/GEJ tumors, with > 15 examined lymph nodes, and treated at a US center of excellence. On multivariable analysis, KUS (HR 2.80, p < 0.001) and W (HR 5.79, p < 0.001) patients had an increased risk of mortality compared to KK patients. CONCLUSIONS: Both the place of birth and the place of treatment significantly contribute to the improved prognosis of patients with gastric cancer in Korea relative to those in the US, implicating both nature and nurture in this phenomenon.

Lower phosphate levels following pancreatectomy is associated with postoperative pancreatic fistula formation.

BACKGROUND: Whereas hypophosphatemia following hepatectomy is associated with decreased morbidity, hypophosphatemia following pancreatectomy may be associated with increased morbidity, including the development of postoperative pancreatic fistula (POPF). This study aimed to evaluate the relationship between postoperative hypophosphatemia and POPF formation. METHODS: Patients from our institutional Research Patient Data Registry who underwent pancreatectomy from 2001 to 2017 were included. POPF was defined according to the International Study Group for Pancreatic Fistulas (ISGPF) criteria and according to internal criteria for drain removal. Postoperative serum phosphate levels, demographics, and comorbidities were evaluated. Unadjusted and adjusted analyses were performed. RESULTS: 2342 patients underwent pancreatic resection. Mean age was 63.0 years (SD 14.3), 51.2% were male, and 58.7% had pancreatic cancer. Of all resections, 67.7% were pancreaticoduodenectomies. In unadjusted analysis, phosphate levels were significantly and persistently lower on POD 0 and POD 2-5 in patients who developed POPF's. In adjusted analysis, POD 2 phosphate <1.75 predicted an additional 46% increased odds of POPF (OR 1.46 95% CI 1.06-2.01; p = 0.02). Distal pancreatectomy was independently associated with POPF formation when compared to pancreaticoduodenectomy (OR 1.72 95% CI 1.18-2.51; p = 0.005). CONCLUSION: Lower phosphate levels in the early post-operative period following both proximal and distal pancreatectomies is associated with increased risk of POPF.

Most ApoL1 Is Secreted by the Liver.

Two coding sequence variants in the APOL1 gene (G1 and G2) explain much of the increased risk for FSGS, HIV-associated nephropathy, and hypertension-attributed ESRD among people of recent African ancestry. The ApoL1 protein is expressed in a wide variety of cell tissues. It has been assumed that the majority of circulating ApoL1 is produced by the liver, but this has not been shown. Using mass spectrometry, we genotyped and quantified the circulating ApoL1 in two liver transplant recipients whose native APOL1 genotype differed from the genotype of the deceased donors, allowing us to differentiate liver- from nonliver-produced ApoL1. Our findings confirm that the liver is indeed the main source of circulating ApoL1. However, the liver is not the sole source of circulating ApoL1, because we found that residual amounts of native ApoL1 continued to circulate in the blood, even after the liver transplant.

An Online Tool for Global Benchmarking of Risk-Adjusted Surgical Outcomes.

BACKGROUND: Increasing evidence demonstrates significant variation in adverse outcomes following surgery between countries. In order to better quantify these variations, we hypothesize that freely available online risk calculators can be used as a tool to generate global benchmarking of risk-adjusted surgical outcomes. METHODS: This is a prospective cohort study conducted at an academic teaching hospital in South Africa (GSH). Consecutive adult patients undergoing major general or vascular surgery who met the ACS-NSQIP inclusion criteria for a 3-month period were included. Data variables required by the ACS risk calculator were prospectively collected, and patients were followed for 30 days post-surgery for the occurrence of endpoints. Calculating observed-to-expected ratios for ten outcome measures of interest generated risk-adjusted outcomes benchmarked against the ACS-NSQIP consortium. RESULTS: A total of 373 major general and vascular surgery procedures met the inclusion criteria. The GSH operative cohort varied significantly compared to the 2012 ACS-NSQIP database. The risk-adjusted O/E ratios were significant for any complication O/E 1.91 (95 % CI 1.57-2.31), surgical site infections O/E 4.76 (95 % CI 3.71-6.01), renal failure O/E 3.29 (95 % CI 1.50-6.24), death O/E 3.43 (95 % CI 2.19-5.11), and total length of stay (LOS) O/E 3.43 (95 % CI 2.19-5.11). CONCLUSION: Freely available online risk calculators can be utilized as tools for global benchmarking of risk-adjusted surgical outcomes.

Impact of EGF, IL28B, and PNPLA3 polymorphisms on the outcome of allograft hepatitis C: a multicenter study.

Hepatitis C virus (HCV) infection is accelerated following liver transplantation (LT). Single nucleotide polymorphisms (SNPs) near the epidermal growth factor (EGF) (rs4444903), IL28B (rs12979860), and PNPLA3 (rs738409) loci are associated with treatment response, fibrosis, and hepatocellular carcinoma in non-transplant hepatitis C, but allograft population data are limited. We sought to determine the role of these SNPs in 264 patients with HCV who underwent LT between 1990 and 2008. Genotypes were determined from donor wedge/allograft biopsies and recipient explants. Cox proportional hazards model was used to assess time to cirrhosis, liver-related death, and retransplantation, adjusting for donor age and sustained virological response (SVR). Over a median follow-up of 6.3 yr, a trend toward increased progression to graft cirrhosis was observed among recipients of an EGF non-AA vs. AA donor liver (adjusted HR 2.01; 95% CI 0.93-4.34; p = 0.08). No other genotypes predicted cirrhosis development or graft survival. The CC IL28B variant in both recipients and donors was associated with increased rate of SVR (R-CC/D-CC 8/12[67%], R-non-CC/D-CC or R-CC/D-non-CC 23/52[44%], R-non-CC/D-non-CC 12/45[27%], p linear trend = 0.009). Recipient EGF, IL28B, and PNPLA3, and donor IL28B and PNPLA3 genotypes do not predict adverse outcomes in HCV LT recipients. A potential association exists between donor EGF genotype and cirrhosis.

Reduced Albumin Dosing During Large-Volume Paracentesis Is Not Associated with Adverse Clinical Outcomes.

BACKGROUND: LVP is used to manage diuretic-resistant ascites in cirrhotic patients. Albumin administration prevents complications including acute kidney injury and paracentesis-induced circulatory dysfunction, but the optimal dose is unclear. AIM: We sought to assess adherence to guidelines enacted in July 2011 at our center for reducing the albumin dose administered at large-volume paracentesis (LVP) and evaluate the cost and rate of complications of LVPs before and after guideline enactment. METHODS: All LVPs performed on cirrhotic patients in our center's Department of Radiology between July 2009 and January 2014 were studied. Outcomes included adherence to guidelines, LVP complications, and administered albumin cost. Groups were compared using Student's t tests for continuous data and Chi-square or Fisher's exact tests for categorical data. A repeated measurements model accounted for patients with multiple LVPs. RESULTS: Of the 935 LVPs, 288 occurred before guideline implementation (group 1) and 647 occurred after (group 2). The mean dose of albumin administered was 13.7 g/L of ascites removed in group 1 versus 10.3 g/L in group 2 (p < 0.0001). Of the group 2 LVPs, 235 (36.3 %) adhered to guidelines. There were no significant differences in LVP complications. CONCLUSIONS: Guidelines were followed in one-third of LVPs. Despite this limited adherence, a reduction in albumin administration and associated cost savings was still observed. There was no increase in LVP-related complications after guideline implementation or in the adherent group, suggesting that albumin dose can be safely reduced. Future efforts should be directed at enhancing guideline adherence and potentially further reducing albumin dosing.

Agrin Inhibition in Enteric Neural Stem Cells Enhances Their Migration Following Colonic Transplantation.

Regenerative cell therapy to replenish the missing neurons and glia in the aganglionic segment of Hirschsprung disease represents a promising treatment option. However, the success of cell therapies for this condition are hindered by poor migration of the transplanted cells. This limitation is in part due to a markedly less permissive extracellular environment in the postnatal gut than that of the embryo. Coordinated interactions between enteric neural crest-derived cells (ENCDCs) and their local environment drive migration along the embryonic gut during development of the enteric nervous system. Modifying transplanted cells, or the postnatal extracellular environment, to better recapitulate embryonic ENCDC migration could be leveraged to improve the engraftment and coverage of stem cell transplants. We compared the transcriptomes of ENCDCs from the embryonic intestine to that of postnatal-derived neurospheres and identified 89 extracellular matrix (ECM)-associated genes that are differentially expressed. Agrin, a heparin sulfate proteoglycan with a known inhibitory effect on ENCDC migration, was highly over-expressed by postnatal-derived neurospheres. Using a function-blocking antibody and a shRNA-expressing lentivirus, we show that inhibiting agrin promotes ENCDC migration in vitro and following cell transplantation ex vivo and in vivo. This enhanced migration is associated with an increased proportion of GFAP + cells, whose migration is especially enhanced.

Mature enteric neurons have the capacity to reinnervate the intestine with glial cells as their guide.

Here, we establish that plasticity exists within the postnatal enteric nervous system by demonstrating the reinnervation potential of post-mitotic enteric neurons (ENs). Employing BAF53b-Cre mice for selective neuronal tracing, the reinnervation capabilities of mature postnatal ENs are shown across multiple model systems. Isolated ENs regenerate neurites in vitro, with neurite complexity and direction influenced by contact with enteric glial cells (EGCs). Nerve fibers from transplanted ENs exclusively interface and travel along EGCs within the muscularis propria. Resident EGCs persist after Cre-dependent ablation of ENs and govern the architecture of the myenteric plexus for reinnervating ENs, as shown by nerve fiber projection tracing. Transplantation and optogenetic experiments in vivo highlight the rapid reinnervation potential of post-mitotic neurons, leading to restored gut muscle contractile activity within 2 weeks. These studies illustrate the structural and functional reinnervation capacity of post-mitotic ENs and the critical role of EGCs in guiding and patterning their trajectories.

Resolving Resident Colonic Muscularis Macrophage Diversity and Plasticity During Colitis.

BACKGROUND: Immune cell populations in the intestinal muscularis propria during colitis are poorly resolved. Maintaining homeostasis in this niche is critical, highlighted by the poorer prognosis of inflammatory bowel disease associated with muscularis propria inflammation. METHODS: This study utilizes single-cell RNA sequencing to survey the immune cell populations within the muscularis propria of normal colon and dextran sodium sulfate-induced colitis. Findings are validated by immunohistochemistry, flow cytometry and cell-lineage tracing in vivo, and in vitro assays with muscularis macrophages (MMφ). RESULTS: In naïve conditions, transcriptional duality is observed in MMφs with 2 major subpopulations: conventional resident Cx3cr1+ MMφs and Lyve1+ MMφs. The Lyve1+ population is phagocytic and expresses several known MMφ markers in mouse and human, confirming their identity as a bona fide MMφ subset. Single-cell transcriptomics indicate that resident MMφs are retained during colitis and exhibit plasticity toward an inflammatory profile. Lyve1+ MMφs, which express anti-inflammatory marker CD163, are absent during colitis, as confirmed by flow cytometry. In contrast, lineage tracing finds that resident Cx3cr1+ MMφs remain during colitis and are not completely replaced by the inflammatory infiltrating monocytes. In vitro studies provide biological evidence of the plasticity of resident Cx3cr1+ MMφs in response to lipopolysaccharide (LPS), mirroring transcriptional observations in vivo of their inflammatory plasticity. Potential markers for colitic MMφs, validated in animal models and in individuals with ulcerative colitis, are identified. CONCLUSIONS: Our findings contribute to the understanding of the immune system in the muscularis propria niche during colitis by resolving the heterogeneity and origins of colitic MMφs.

Involvement of the muscularis propria accompanies a poorer prognosis in IBD. This study characterizes muscularis macrophage subpopulations during colitis, highlighting the loss of anti-inflammatory LYVE-1+ macrophages and inflammatory plasticity in resident CX3CR1+ macrophages, providing insights into prognostic and therapeutic targets.

The molecular structure of and interconversion tunneling in the argon-cis-1,2-difluoroethylene complex.

Guided by ab initio predictions, the structure of the gas-phase complex formed between cis-1,2-difluoroethylene and an argon atom in a pulsed molecular jet is determined using microwave spectroscopy in the 5.7-21.5 GHz region of the spectrum. This is a non-planar, symmetric species, with the argon atom located in the FCCF cavity of the difluoroethylene. The transitions in the microwave spectrum are observed to be split by an interconversion tunneling motion between the two equivalent configurations for the complex with the argon atom located either above or below the difluoroethylene molecular plane. Both one- and two-dimensional discrete variable representation calculations of the tunneling splitting using the ab initio interaction potential for the complex suggest that the barrier to interconversion is overestimated by theory.

Differentiated neuroblastoma cells remain epigenetically poised for de-differentiation to an immature state.

Neuroblastoma is the most common extracranial solid tumor of childhood and accounts for a significant share of childhood cancer deaths. Prior studies utilizing RNA sequencing of bulk tumor populations showed two predominant cell states characterized by high and low expression of neuronal genes. Although cells respond to treatment by altering their gene expression, it is unclear whether this reflects shifting balances of distinct subpopulations or plasticity of individual cells. Using mouse and human neuroblastoma cell lines lacking MYCN amplification, we show that the antigen CD49b (also known as ITGA2) distinguishes these subpopulations. CD49b expression marked proliferative cells with an immature gene expression program, whereas CD49b-negative cells expressed differentiated neuronal marker genes and were non-cycling. Sorted populations spontaneously switched between CD49b expression states in culture, and CD49b-negative cells could generate rapidly growing, CD49b-positive tumors in mice. Although treatment with the chemotherapy drug doxorubicin selectively killed CD49b-positive cells in culture, the CD49b-positive population recovered when treatment was withdrawn. We profiled histone 3 (H3) lysine 27 acetylation (H3K27ac) to identify enhancers and super enhancers that were specifically active in each population and found that CD49b-negative cells maintained the priming H3 lysine 4 methylation (H3K4me1) mark at elements that were active in cells with high expression of CD49b. Improper maintenance of primed enhancer elements might thus underlie cellular plasticity in neuroblastoma, representing potential therapeutic targets for this lethal tumor.

Association for Academic Surgery/Society of University Surgeons research awards are highly successful in fostering future surgeon-scientists.

BACKGROUND: The surgeon-scientist brings a unique perspective to surgical research. The Association of Academic Surgeons and Society of University Surgeons foster the development of surgeon-scientists through foundation awards to residents and junior faculty. We sought to evaluate the academic success of surgeons who received an Association for Academic Surgery/Society of University Surgeons award. METHODS: Information was collected for individuals who received a resident or junior faculty research award from the Association for Academic Surgery or Society of University Surgeons. Google Scholar, Scopus, and the National Institutes of Health Research Portfolio Online Reporting Tools: Expenditures and Results were used to assess scholarly achievements. RESULTS: Eighty-two resident awardees were included, 31 (38%) of whom were female. Thirteen (24%) are now professors, 12 (22%) are division chiefs, and 4 (7%) are department chairs. Resident awardees have a median of 886 citations (interquartile range 237-2,111) and an H-index of 14 (interquartile range 7-23). Seven (13%) went on to receive K08/K23 awards, and 7 (13%) received R01s, with a total of about $200 million in National Institutes of Health funding (79-fold return on investment). Thirty-four junior faculty awardees were included, 10 (29%) of whom were female. Thirteen (38%) are now professors, 12 (35%) are division chiefs, and 7 (21%) are department chairs. Faculty awardees have a median of 2,617 citations (interquartile range 1,343-7,857) and an H-index of 25 (interquartile range 18-49). Four (12%) received K08 or K23 awards, and 10 (29%) received R01s, with about $139 million in National Institutes of Health funding (98-fold return on investment). CONCLUSION: Association for Academic Surgery/Society of University Surgeons research awardees experience high degrees of success in academic surgery. Most resident awardees pursue fellowship training and remain in academic surgery. A high percentage of both faculty and resident awardees hold leadership positions and successfully achieve National Institutes of Health funding.

Single-cell multiome sequencing clarifies enteric glial diversity and identifies an intraganglionic population poised for neurogenesis.

The enteric nervous system (ENS) consists of glial cells (EGCs) and neurons derived from neural crest precursors. EGCs retain capacity for large-scale neurogenesis in culture, and in vivo lineage tracing has identified neurons derived from glial cells in response to inflammation. We thus hypothesize that EGCs possess a chromatin structure poised for neurogenesis. We use single-cell multiome sequencing to simultaneously assess transcription and chromatin accessibility in EGCs undergoing spontaneous neurogenesis in culture, as well as small intestine myenteric plexus EGCs. Cultured EGCs maintain open chromatin at genomic loci accessible in neurons, and neurogenesis from EGCs involves dynamic chromatin rearrangements with a net decrease in accessible chromatin. A subset of in vivo EGCs, highly enriched within the myenteric ganglia and that persist into adulthood, have a gene expression program and chromatin state consistent with neurogenic potential. These results clarify the mechanisms underlying EGC potential for neuronal fate transition.

The science of Hirschsprung disease: What we know and where we are headed.

The enteric nervous system (ENS) is a rich network of neurons and glial cells that comprise the gastrointestinal tract's intrinsic nervous system and are responsible for controlling numerous complex functions, including digestion, transit, secretion, barrier function, and maintenance of a healthy microbiome. Development of a functional ENS relies on the coordinated interaction between enteric neural crest-derived cells and their environment as the neural crest-derived cells migrate rostrocaudally along the embryonic gut mesenchyme. Congenital or acquired disruption of ENS development leads to various neurointestinal diseases. Hirschsprung disease is a congenital neurocristopathy, a disease of the neural crest. It is characterized by a variable length of distal colonic aganglionosis due to a failure in enteric neural crest-derived cell proliferation, migration, differentiation, and/or survival. In this review, we will review the science of Hirschsprung disease, targeting an audience of pediatric surgeons. We will discuss the basic biology of normal ENS development, as well as what goes awry in ENS development in Hirschsprung disease. We will review animal models that have been integral to studying this disease, as well as current hot topics and future research, including genetic risk profiling, stem cell therapy, non-invasive diagnostic techniques, single-cell sequencing techniques, and genotype-phenotype correlation.

Applications of Single-Cell Sequencing Technology to the Enteric Nervous System.

With recent technical advances and diminishing sequencing costs, single-cell sequencing modalities have become commonplace. These tools permit analysis of RNA expression, DNA sequence, chromatin structure, and cell surface antigens at single-cell resolution. Simultaneous measurement of numerous parameters can resolve populations including rare cells, thus revealing cellular diversity within organs and permitting lineage reconstruction in developing tissues. Application of these methods to the enteric nervous system has yielded a wealth of data and biological insights. We review recent papers applying single-cell sequencing tools to the nascent neural crest and to the developing and mature enteric nervous system. These studies have shown significant diversity of enteric neurons and glia, suggested paradigms for neuronal specification, and revealed signaling pathways active during development. As technology evolves and multiome techniques combining two or more of transcriptomic, genomic, epigenetic, and proteomic data become prominent, we anticipate these modalities will become commonplace in ENS research and may find a role in diagnostic testing and personalized therapeutics.

Peripheral nervous system: A promising source of neuronal progenitors for central nervous system repair.

With a steadily aging population there is an increasing prevalence of neurological disorders. Given the lack of effective treatment strategies and a limited ability for the central nervous system (CNS) to regenerate endogenously, there is a critical need to better understand exogenous strategies for nervous system repair. Stem cell therapy offers a promising approach to promote the repair of neurologic tissue and function, however studies to date have been limited by various factors including challenges in harvesting donor cells from the CNS, ethical concerns regarding use of embryonic or fetal tissue, tumorigenic potential of induced pluripotent stem cells, and immune-mediated rejection of non-autologous cell sources. Here we review and propose two alternative sources of autologous cells derived from the peripheral nervous system (PNS) for CNS repair: enteric neuronal stem cells (ENSCs) and neural crest-derived Schwann cells found in subcutaneous adipose tissue (termed SAT-NSCs). ENSCs can be successfully isolated from the postnatal enteric nervous system, propagated in vitro, and transplanted successfully into models of CNS injury via both direct intracerebral injection and systemic tail vein injection. Similarly, SAT-NSCs can be readily isolated from both human and mouse adipose tissue and, although not yet utilized in models of CNS injury, have successfully been transplanted and restored function in models of colonic aganglionosis and gastroparesis. These unique sources of PNS-derived autologous cells offer an exciting option for stem cell therapies for the CNS as they have proven neurogenic potential and eliminate concerns around tumorigenic risk, ethical considerations, and immune-mediated rejection.