Assessment of longitudinal changes in body composition of children with lymphoma and rhabdomyosarcoma.

BACKGROUND: Studies examining changes in skeletal muscle and adipose tissue during treatment for cancer in children, adolescents, and young adults and their effect on the risk of chemotherapy toxicity (chemotoxicity) are limited. METHODS: Among 78 patients with lymphoma (79.5%) and rhabdomyosarcoma (20.5%), changes were measured in skeletal muscle (skeletal muscle index [SMI]; skeletal muscle density [SMD]) and adipose tissue (height-adjusted total adipose tissue [hTAT]) between baseline and first subsequent computed tomography scans at the third lumbar vertebral level by using commercially available software. Body mass index (BMI; operationalized as a percentile [BMI%ile]) and body surface area (BSA) were examined at each time point. The association of changes in body composition with chemotoxicities was examined by using linear regression. RESULTS: The median age at cancer diagnosis of this cohort (62.8% male; 55.1% non-Hispanic White) was 12.7 years (2.5-21.1 years). The median time between scans was 48 days (range, 8-207 days). By adjusting for demographics and disease characteristics, this study found that patients undergo a significant decline in SMD (ß ± standard error [SE] = -4.1 ± 1.4; p < .01). No significant changes in SMI (ß ± SE = -0.5 ± 1.0; p = .7), hTAT (ß ± SE = 5.5 ± 3.9; p = .2), BMI% (ß ± SE = 4.1 ± 4.8; p = .3), or BSA (ß ± SE = -0.02 ± 0.01; p = .3) were observed. Decline in SMD (per Hounsfield unit) was associated with a greater proportion of chemotherapy cycles with grade ≥3 nonhematologic toxicity (ß ± SE = 1.09 ± 0.51; p = .04). CONCLUSIONS: This study shows that children, adolescents, and young adults with lymphoma and rhabdomyosarcoma undergo a decline in SMD early during treatment, which is associated with a risk of chemotoxicities. Future studies should focus on interventions designed at preventing the loss of muscle during treatment. PLAIN LANGUAGE SUMMARY: We show that among children, adolescents, and young adults with lymphoma and rhabdomyosarcoma receiving chemotherapy, skeletal muscle density declines early during treatment. Additionally, a decline in skeletal muscle density is associated with a greater risk of nonhematologic chemotoxicities.

Risk of COVID-19 infection in long-term survivors of blood or marrow transplantation: a BMTSS report.

There is limited information regarding COVID-19 in long-term blood or marrow transplant (BMT) survivors. We leveraged the BMT Survivor Study (BMTSS) to address this gap. BMTSS included patients who underwent BMT at 1 of 3 sites in the United States between 1974 and 2014 and survived ≥2 years after BMT. A sibling cohort serves as a non-BMT comparison group. Participants (2430 BMT survivors; 780 non-BMT participants) completed the BMTSS survey between October 2020 and November 2021 about COVID-19 testing, risk mitigation behaviors, morbidity, and health care use. Median age at BMT was 46 years (range, 0-78 years) and median follow-up since BMT was 14 years (6-46 years); 76% were non-Hispanic White, 54% had received allogeneic BMT. The risk of COVID-19 infection was comparable for BMT survivors vs non-BMT participants (15-month cumulative incidence, 6.5% vs 8.1%; adjusted odd ratio [aOR] = 0.93; 95% confidence interval [CI], 0.65-1.33; P = .68). Among survivors, being unemployed (aOR 1.90; 95% CI, 1.12-3.23; P = .02; reference: retired) increased the odds of infection; always wearing a mask in public was protective (aOR = 0.49; 95% CI, 0.31-0.77; P = .002; reference: not always masking). When compared with COVID-positive non-BMT participants, COVID-positive BMT survivors had higher odds of hospitalization (aOR = 2.23; 95% CI, 0.99-5.05; P = .05); however, the odds of emergency department visits were comparable (aOR = 1.60; 95% CI = 0.71-3.58; P = .25). COVID-19 infection status did not increase the odds of hospitalization among BMT survivors (aOR = 1.32; 95% CI = 0.89-1.95; P = .17) but did increase the odds of emergency department visits (aOR = 2.63; 95% CI, 1.74-3.98; P <.0001). These findings inform health care providers about the management of care for long-term BMT survivors during the ongoing pandemic.

Neighborhood disadvantage, health status, and health care utilization after blood or marrow transplant: BMTSS report.

Living in a disadvantaged neighborhood is associated with poor health outcomes. Blood or Marrow Transplant (BMT) survivors remain at risk of chronic health conditions requiring anticipatory management. We hypothesized that among BMT survivors, neighborhood disadvantage was associated with poor self-reported routine health care utilization and health. We leveraged data from BMTSS - a retrospective cohort study examining long-term outcomes among individuals surviving ≥2 y following BMT at three institutions between 1974 and 2014. Participants in this analysis completed the BMTSS survey (sociodemographics; chronic health conditions; time since routine check-up; self-reported health). The Area Deprivation Index (ADI) represented neighborhood disadvantage; this composite indicator of 17 census measures is a percentile rank (0 = least deprived to 100 = most deprived). Multivariable ordered logit regression adjusted for clinical factors and individual-level sociodemographics, modeling associations between ADI, time since routine check-up, and self-reported health. Among 2,857 survivors, median ADI was 24 (interquartile range: 10-46). Adjusting for self-reported individual-level socioeconomic indicators and chronic health conditions, patients in more disadvantaged neighborhoods had higher odds of reporting longer intervals since routine check-up (ORADI_continuous = 1.007, P < .001) and poorer health status (controlling for time since check-up; ORADI_continuous = 1.005, P = .003). Compared with patients living in the least disadvantaged neighborhood (ADI = 1), patients in the most disadvantaged neighborhood (ADI = 100), had twice the odds (ORADI = 1.007^99 = 2.06) of reporting no routine visits and 1.65-times the odds of reporting poor health (ORADI = 1.005^99 = 1.65). In BMT survivors, access to health care and health status are associated with area disadvantage. These findings may inform strategies to address long-term care coordination and retention for vulnerable survivors.

Financial Burden in Blood or Marrow Transplantation Survivors During the COVID-19 Pandemic: A BMTSS Report.

PURPOSE: The financial burden experienced by blood or marrow transplant (BMT) survivors during the COVID-19 pandemic remains unstudied. We evaluated the risk for high out-of-pocket medical costs and associated financial burden experienced by BMT survivors and a sibling comparison group during the COVID-19 pandemic. METHODS: This study included 2,370 BMT survivors and 750 siblings who completed the BMT Survivor Study survey during the pandemic. Participants reported employment status, out-of-pocket medical costs, and financial burden. Medical expenses ≥ 10% of the annual household income constituted high out-of-pocket medical costs. Logistic regression identified factors associated with high out-of-pocket medical costs and financial burden. RESULTS: BMT survivors were more likely to incur high out-of-pocket medical costs (11.3% v 3.1%; adjusted odds ratio [aOR], 2.88; 95% CI, 1.84 to 4.50) than the siblings. Survivor characteristics associated with high out-of-pocket medical costs included younger age at study (aORper_year_younger_age, 1.02; 95% CI, 1.00 to 1.03), lower prepandemic annual household income and/or education (< $50,000 US dollars and/or < college graduate: aOR, 1.96; 95% CI, 1.42 to 2.69; reference: ≥ $50,000 in US dollars and ≥ college graduate), > 1 chronic health condition (aOR, 2.82; 95% CI, 2.00 to 3.98), ≥ 1 hospitalization during the pandemic (aOR, 2.11; 95% CI, 1.53 to 2.89), and being unemployed during the pandemic (aOR, 1.52; 95% CI, 1.06 to 2.17). Among BMT survivors, high out-of-pocket medical costs were significantly associated with problems in paying medical bills (aOR, 10.57; 95% CI, 7.39 to 15.11), deferring medical care (aOR, 4.93; 95% CI, 3.71 to 6.55), taking a smaller dose of medication than prescribed (aOR, 4.99; 95% CI, 3.23 to 7.70), and considering filing for bankruptcy (aOR, 3.80; 95% CI, 2.14 to 6.73). CONCLUSION: BMT survivors report high out-of-pocket medical costs, which jeopardizes their health care and may affect health outcomes. Policies aimed at reducing financial burden in BMT survivors, such as expanding access to patient assistance programs, may mitigate the negative health consequences.

Lance Adams Syndrome After Hypoxic Cardiac Arrest: A Case Report.

Lance-Adams syndrome (chronic post-hypoxic myoclonus) is a rare syndrome occurring in patients after cardiopulmonary resuscitation. Awareness of this condition is important to distinguish it from myoclonic status epilepticus, which is a poor prognostic sign. We present the case of a 32-year-old woman who developed Lance-Adams syndrome after an episode of hypoxic cardiac arrest from severe pneumonia. Brain computed tomography, magnetic resonance imaging, and an electroencephalogram were used to rule out other causes of myoclonus. In this report, we discuss the diagnosis, treatment, and prognosis of patients with Lance-Adams syndrome.

Trends in Late Mortality and Life Expectancy After Autologous Blood or Marrow Transplantation Over Three Decades: A BMTSS Report.

PURPOSE: We determined trends in life expectancy and cause-specific late mortality after autologous blood or marrow transplantation (BMT) performed over a 30-year period, using the BMT Survivor Study. METHODS: We constructed a cohort of 4,702 individuals with hematologic neoplasms who lived ≥ 2 years after autologous BMT performed between 1981 and 2014 at three transplant centers. The end of follow-up was April 19, 2021. The primary exposure variable was autologous BMT performed in four eras: 1981-1999; 2000-2005; 2006-2010; and 2011-2014. Vital status and cause of death were obtained from National Death Index Plus program and Accurinct databases. RESULTS: The median age at BMT was 53 years (range, 0-78 years), 58.7% were male, 67.8% were non-Hispanic White, and 28.3% had undergone transplantation between 2011 and 2014. Autologous BMT recipients experienced a 7-year reduction in life expectancy. The adjusted hazard of 5-year all-cause mortality declined over the four eras (reference: 1981-1999; hazard ratio [HR]2000-2005 = 0.77; 95% CI, 0.62 to 0.94; HR2006-2010 = 0.64; 95% CI, 0.51 to 0.79; HR2011-2014 = 0.56; 95% CI, 0.45 to 0.71; Ptrend < .001), as did years of life lost (5.0 years to 1.6 years). The reduction in all-cause mortality was most pronounced among those transplanted for Hodgkin lymphoma or plasma cell dyscrasias, but was not observed among those transplanted for non-Hodgkin lymphoma or those conditioned with total-body irradiation. We also observed a decline in late deaths because of infection (Ptrend < .0001; primarily for BMTs before 2006) and subsequent neoplasms (Ptrend = .03; confined to decline in therapy-related myeloid neoplasm-related mortality) but not because of cardiovascular or renal disease. CONCLUSION: Late mortality among autologous BMT recipients has declined over a 30-year period. However, ongoing efforts are needed to mitigate development of infections, subsequent neoplasms, and cardiovascular and renal disease to further reduce late mortality.

Polycyclic aromatic hydrocarbons regulate the pigmentation pathway and induce DNA damage responses in keratinocytes, a process driven by systemic immunity.

BACKGROUND: Urban pollution is correlated with an increased prevalence of skin pigmentation disorders, however the physiological processes underlying this association are unclear. OBJECTIVES: To delineate the relationship between polycyclic aromatic hydrocarbons (PAHs), a key constituent of atmospheric pollution, and immunity/skin pigmentation pathways. METHODS: We exposed peripheral blood mononuclear cells (PBMC) to PAHs and performed cytokines/chemokine profiling. We then examined the effect of immune activation on pigmentation by co-culturing PBMC and Benzo(a)pyrene (BaP) with reconstructed human pigmented epidermis (RHPE). To study the mechanism, we treated keratinocytes with conditioned medium from BaP-exposed PBMC and studied DNA damage responses, aryl hydrocarbon receptor (AhR) activation and pro-pigmentation factor, proopiomelanocortin (POMC) secretion. RESULTS: PAHs induced up-regulation of inflammatory cytokines/chemokine in PBMC. Co-culturing of RHPE with PBMC+BaP resulted in increased melanin content and localization. BaP-conditioned medium significantly increased DNA damage, p53 stabilization, AhR activation and POMC secretion in keratinocytes. We found that IFNγ induced DNA damage, while TNFα and IL-8 potentiated POMC secretion in keratinocytes. Importantly, BaP-conditioned medium-induced DNA damage and POMC secretion is prevented by antioxidants vitamin E, vitamin C and sulforaphane, as well as the prototypical corticosteroid dexamethasone. Finally, vitamin C and sulforaphane enhanced the genome protective and depigmentation effects of dexamethasone, providing proof-of-concept for a combinatorial approach for the prevention and/or correction of PAH-induced pigment spots formation. CONCLUSION: Our study reveals the importance of systemic immunity in regulating PAH-induced skin pigmentation, and provide a new keratinocyte DNA damage response mechanistic target for the prevention or reversal of pollution-associated skin pigmentation.

Single-cell analysis of human skin identifies CD14+ type 3 dendritic cells co-producing IL1B and IL23A in psoriasis.

Inflammatory skin diseases including atopic dermatitis (AD) and psoriasis (PSO) are underpinned by dendritic cell (DC)-mediated T cell responses. Currently, the heterogeneous human cutaneous DC population is incompletely characterized, and its contribution to these diseases remains unclear. Here, we performed index-sorted single-cell flow cytometry and RNA sequencing of lesional and nonlesional AD and PSO skin to identify macrophages and all DC subsets, including the newly described mature LAMP3+BIRC3+ DCs enriched in immunoregulatory molecules (mregDC) and CD14+ DC3. By integrating our indexed data with published skin datasets, we generated a myeloid cell universe of DC and macrophage subsets in healthy and diseased skin. Importantly, we found that CD14+ DC3s increased in PSO lesional skin and co-produced IL1B and IL23A, which are pathological in PSO. Our study comprehensively describes the molecular characteristics of macrophages and DC subsets in AD and PSO at single-cell resolution, and identifies CD14+ DC3s as potential promoters of inflammation in PSO.

Spontaneous Epidural Hematoma of the Cervical Spine in an Elderly Woman with Recent COVID-19 Infection: A Case Report.

BACKGROUND This report presents the case of a woman with no known coagulopathy, use of anticoagulants, or history of trauma who spontaneously developed an epidural hematoma of the spine. This is an uncommon condition, with the potential for missed diagnosis and potential harm to the patient. CASE REPORT The patient was an elderly woman with a history of Type 2 diabetes mellitus and hyperlipidemia. Of note, she had recently recovered from COVID-19. Because the woman presented with right-sided weakness and pain in the back of her neck, the stroke team was activated. A computed tomography (CT) scan of her neck revealed a very subtle hyperdensity, which on further investigation was found to be an acute epidural hematoma at C2-C3 space through the C6 vertebra. While awaiting surgery, the patient had spontaneous improvement of her right-sided weakness and her condition eventually was managed conservatively. CONCLUSIONS Spontaneous spinal epidural hematoma is an uncommon condition, and a high index of suspicion is required to accurately diagnose and appropriately manage it. In the case presented here, the hematoma was subtle on the CT scan, and the patient's weakness easily could have been misdiagnosed as an ischemic stroke. That may have resulted in administration of thrombolytics, potentially causing significant harm. In addition, the patient had recently recovered from COVID-19 disease, which may or may not be incidental. Further observation will be required to determine if there is a spike in similar cases, which may be temporally associated with the novel coronavirus.

The COSMIC Bubble Helmet: A Non-Invasive Positive Pressure Ventilation System for COVID-19.

Goal: COSMIC Medical, a Vancouver-based open-source volunteer initiative, has designed an accessible, affordable, and aerosol-confining non-invasive positive-pressure ventilator (NIPPV) device, known as the COSMIC Bubble Helmet (CBH). This device is intended for COVID-19 patients with mild-to-moderate acute respiratory distress syndrome. System Design: CBH is composed of thermoplastic polyurethane, which creates a flexible neck seal and transparent hood. This device can be connected to wall oxygen, NIPPVs including Continuous Positive Airway Pressure and Bi-level Positive Airway Pressure, and mechanical ventilators. Discussion: Justification of CBH design components relied on several factors, predominantly the safety and comfort of patients and healthcare providers. Conclusion: CBH has implications within and outside of the pandemic, as an alternative to invasive mechanical ventilation methods. We have experimentally verified that CBH is effective in minimizing aerosolization risks and performs at specified clinical requirements.

Cone Contrast Test for Color Vision Deficiency Screening Among a Cohort of Military Aircrew Applicants.

PURPOSE: To evaluate the use of the Cone Contrast Test (CCT) as a color vision screening tool in an Asian population of aircrew applicants and compare it against the Ishihara Psuedo Isochromatic Plates (PIP) - Edridge Lantern Test (ELT) screening pathway, assessing its impact on attrition with CCT cut-off scores of 55 and 75.METHODS: This is a retrospective review of 862 Republic of Singapore Airforce aircrew applicants tested with CCT and Ishihara PIP-ELT combination as screening. CCT repeatability was analyzed by comparing the subject's interocular (right vs. left eye) scores measured as the coefficient of repeatability (COR), with COR differing by ≥15 points considered to be outside normal limits.RESULTS: Of the applicants, 17 (1.97%) failed to achieve a CCT score of ≥55 (5 protan, 12 deutan), while 26 (3.02%) applicants failed to achieve a score ≥75 (5 protan, 21 deutan). Of the 17 applicants who obtained a CCT score of <55, 16 failed the Ishihara PIP test. The only applicant who passed the Ishihara PIP test had a CCT score of 50. Of all applicants, 1.7% had a COR of ≥15, with 93.3% of them identified as color vision deficient (CVD). Our results demonstrated excellent test repeatability, with 99.9% (835 out of 836) of color vision normal (CVN) applicants achieving a COR of <15 points.CONCLUSION: Our study demonstrated a high correlation between the CCT (passing score of ≥55) and the Ishihara PIP. Employing the CCT with a passing score of ≥75, instead of the Ishihara PIP-ELT combination, led to an increase in attrition rate of 0.7-3.0%.Chay IW, Lim SWY, Tan BBC. Cone Contrast Test for color vision deficiency screening among a cohort of military aircrew applicants. Aerosp Med Hum Perform. 2019; 90(2):71-76.

ENPP1 Mutation Causes Recessive Cole Disease by Altering Melanogenesis.

Cole disease is a genodermatosis of pigmentation following a strict dominant mode of inheritance. In this study, we investigated eight patients affected with an overlapping genodermatosis after recessive inheritance. The patients presented with hypo- and hyperpigmented macules over the body, resembling dyschromatosis universalis hereditaria in addition to punctuate palmoplantar keratosis. By homozygosity mapping and whole-exome sequencing, a biallelic p.Cys120Arg mutation in ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) was identified in all patients. We found that this mutation, like those causing dominant Cole disease, impairs homodimerization of the ENPP1 enzyme that is mediated by its two somatomedin-B-like domains. Histological analysis revealed structural and molecular changes in affected skin that were likely to originate from defective melanocytes because keratinocytes do not express ENPP1. Consistently, RNA-sequencing analysis of patient-derived primary melanocytes revealed alterations in melanocyte development and in pigmentation signaling pathways. We therefore conclude that germline ENPP1 cysteine-specific mutations, primarily affecting the melanocyte lineage, cause a clinical spectrum of dyschromatosis, in which the p.Cys120Arg allele represents a recessive and more severe form of Cole disease.

Induced-Pluripotent-Stem-Cell-Derived Primitive Macrophages Provide a Platform for Modeling Tissue-Resident Macrophage Differentiation and Function.

Tissue macrophages arise during embryogenesis from yolk-sac (YS) progenitors that give rise to primitive YS macrophages. Until recently, it has been impossible to isolate or derive sufficient numbers of YS-derived macrophages for further study, but data now suggest that induced pluripotent stem cells (iPSCs) can be driven to undergo a process reminiscent of YS-hematopoiesis in vitro. We asked whether iPSC-derived primitive macrophages (iMacs) can terminally differentiate into specialized macrophages with the help of growth factors and organ-specific cues. Co-culturing human or murine iMacs with iPSC-derived neurons promoted differentiation into microglia-like cells in vitro. Furthermore, murine iMacs differentiated in vivo into microglia after injection into the brain and into functional alveolar macrophages after engraftment in the lung. Finally, iPSCs from a patient with familial Mediterranean fever differentiated into iMacs with pro-inflammatory characteristics, mimicking the disease phenotype. Altogether, iMacs constitute a source of tissue-resident macrophage precursors that can be used for biological, pathophysiological, and therapeutic studies.

Human Innate Lymphoid Cell Subsets Possess Tissue-Type Based Heterogeneity in Phenotype and Frequency.

Animal models have highlighted the importance of innate lymphoid cells (ILCs) in multiple immune responses. However, technical limitations have hampered adequate characterization of ILCs in humans. Here, we used mass cytometry including a broad range of surface markers and transcription factors to accurately identify and profile ILCs across healthy and inflamed tissue types. High dimensional analysis allowed for clear phenotypic delineation of ILC2 and ILC3 subsets. We were not able to detect ILC1 cells in any of the tissues assessed, however, we identified intra-epithelial (ie)ILC1-like cells that represent a broader category of NK cells in mucosal and non-mucosal pathological tissues. In addition, we have revealed the expression of phenotypic molecules that have not been previously described for ILCs. Our analysis shows that human ILCs are highly heterogeneous cell types between individuals and tissues. It also provides a global, comprehensive, and detailed description of ILC heterogeneity in humans across patients and tissues.

Effectiveness of Hospital Palliative Care Teams for Cancer Inpatients: A Systematic Review.

BACKGROUND: Although the benefits of palliative care in the outpatient setting are well established, there has been little to support the employing of hospital palliative care services for inpatients with cancer. OBJECTIVE: We conducted a systematic literature review to evaluate the effectiveness of palliative care for cancer patients in the acute inpatient hospital setting. METHODS: Two electronic databases-PubMed and CINAHL Plus-were searched for articles published between 1 January 2005 and 28 May 2015. The search was augmented by hand-searches of specific journals and by examining the reference lists of short-listed articles. Studies were included if they evaluated a hospital palliative care service for cancer patients. Data extracted included study design, patient population, study setting, composition of the team, nature of the intervention, outcomes measured, and main findings. RESULTS: No randomized controlled trials were found. There were 14 pre-post studies that evaluated patient outcomes, of which only 2 had a control group. We also reviewed a further seven studies that evaluated other aspects of the palliative care intervention. The studies were not robust enough to confirm the efficacy of hospital palliative care services for cancer patient outcomes. Nonetheless, published studies provide a glimpse into the wider benefits of palliative care interventions. CONCLUSIONS: Data to support the benefit of palliative care interventions in the inpatient acute hospital setting are still lacking. Future studies should employ innovative strategies to further this field of research.

Origin and differentiation of microglia.

Microglia are the resident macrophage population of the central nervous system (CNS). Adequate microglial function is crucial for a healthy CNS. Microglia are not only the first immune sentinels of infection, contributing to both innate and adaptive immune responses locally, but are also involved in the maintenance of brain homeostasis. Emerging data are showing new and fundamental roles for microglia in the control of neuronal proliferation and differentiation, as well as in the formation of synaptic connections. While microglia have been studied for decades, a long history of experimental misinterpretation meant that their true origins remained debated. However, recent studies on microglial origin indicate that these cells in fact arise early during development from progenitors in the embryonic yolk sac (YS) that seed the brain rudiment and, remarkably, appear to persist there into adulthood. Here, we review the history of microglial cells and discuss the latest advances in our understanding of their origin, differentiation, and homeostasis, which provides new insights into their roles in health and disease.

Nanofiber matrices promote the neuronal differentiation of human embryonic stem cell-derived neural precursors in vitro.

The potential of human embryonic stem (ES) cells as experimental therapies for neuronal replacement has recently received considerable attention. In view of the organization of the mature nervous system into distinct neural circuits, key challenges of such therapies are the directed differentiation of human ES cell-derived neural precursors (NPs) into specific neuronal types and the directional growth of axons along specified trajectories. In the present study, we cultured human NPs derived from the NIH-approved ES line BGO1 on polycaprolactone fiber matrices of different diameter (i.e., nanofibers and microfibers) and orientation (i.e., aligned and random); fibers were coated with poly-L-ornithine/laminin to mimic the extracellular matrix and support the adhesion, viability, and differentiation of NPs. On aligned fibrous meshes, human NPs adopt polarized cell morphology with processes extending along the axis of the fiber, whereas NPs on plain tissue culture surfaces or random fiber substrates form nonpolarized neurite networks. Under differentiation conditions, human NPs cultured on aligned fibrous substrates show a higher rate of neuronal differentiation than other matrices; 62% and 86% of NPs become TUJ1 (+) early neurons on aligned micro- and nanofibers, respectively, whereas only 32% and 27% of NPs acquire the same fate on random micro- and nanofibers. Metabolic cell activity/viability studies reveal that fiber alignment and diameter also have an effect on NP viability, but only in the presence of mitogens. Our findings demonstrate that fibrous substrates serve as an artificial extracellular matrix and provide a microenviroment that influences key aspects of the neuronal differentiation of ES-derived NPs.

The effect of nanofiber-guided cell alignment on the preferential differentiation of neural stem cells.

Stem cells display sensitivity to substrate presentation of topographical cues via changes in cell morphology. These biomechanical responses may be transmitted to the nucleus through cytoskeletal-linked signaling pathways. Here we investigate the influence of aligned substratum topography on the cell morphology and subsequently, the neuronal differentiation capabilities of adult neural stem cells (ANSCs). ANSCs that were cultured on aligned fibers elongated along the major fiber axis. Upon induction of differentiation with retinoic acid, a higher fraction of cells on aligned fibers exhibited markers of neuronal differentiation as compared with cells on random fiber or unpatterned surfaces. This effect was in part due to substrate selectivity, whereby aligned fiber substrates were less receptive to the attachment and continued survival of oligodendrocytes than random fiber or unpatterned substrates. Substrate-induced elongation alone was also effective in upregulating canonical Wnt signaling in ANSCs, which was further potentiated by retinoic acid treatment. These findings suggest a mechanism by which morphological control of stem cells operates in concert with biochemical cues for cell fate determination.