All Publications


  • Microglia are effector cells of CD47-SIRPalpha antiphagocytic axis disruption against glioblastoma. Proceedings of the National Academy of Sciences of the United States of America Hutter, G., Theruvath, J., Graef, C. M., Zhang, M., Schoen, M. K., Manz, E. M., Bennett, M. L., Olson, A., Azad, T. D., Sinha, R., Chan, C., Assad Kahn, S., Gholamin, S., Wilson, C., Grant, G., He, J., Weissman, I. L., Mitra, S. S., Cheshier, S. H. 2019

    Abstract

    Glioblastoma multiforme (GBM) is a highly aggressive malignant brain tumor with fatal outcome. Tumor-associated macrophages and microglia (TAMs) have been found to be major tumor-promoting immune cells in the tumor microenvironment. Hence, modulation and reeducation of tumor-associated macrophages and microglia in GBM is considered a promising antitumor strategy. Resident microglia and invading macrophages have been shown to have distinct origin and function. Whereas yolk sac-derived microglia reside in the brain, blood-derived monocytes invade the central nervous system only under pathological conditions like tumor formation. We recently showed that disruption of the SIRPalpha-CD47 signaling axis is efficacious against various brain tumors including GBM primarily by inducing tumor phagocytosis. However, most effects are attributed to macrophages recruited from the periphery but the role of the brain resident microglia is unknown. Here, we sought to utilize a model to distinguish resident microglia and peripheral macrophages within the GBM-TAM pool, using orthotopically xenografted, immunodeficient, and syngeneic mouse models with genetically color-coded macrophages (Ccr2 RFP) and microglia (Cx3cr1 GFP). We show that even in the absence of phagocytizing macrophages (Ccr2 RFP/RFP), microglia are effector cells of tumor cell phagocytosis in response to anti-CD47 blockade. Additionally, macrophages and microglia show distinct morphological and transcriptional changes. Importantly, the transcriptional profile of microglia shows less of an inflammatory response which makes them a promising target for clinical applications.

    View details for PubMedID 30602457

  • Neural tube defects in Uganda: follow-up outcomes from a national referral hospital. Neurosurgical focus Xu, L. W., Vaca, S. D., He, J. Q., Nalwanga, J., Muhumuza, C., Kiryabwire, J., Ssenyonjo, H., Mukasa, J., Muhumuza, M., Grant, G. 2018; 45 (4): E9

    Abstract

    OBJECTIVE: Children with neural tube defects (NTDs) require timely surgical intervention coupled with long-term management by multiple highly trained specialty healthcare teams. In resource-limited settings, outcomes are greatly affected by the lack of coordinated care. The purpose of this study was to characterize outcomes of spina bifida patients treated at Mulago National Referral Hospital (MNRH) through follow-up phone surveys.METHODS: All children presenting to MNRH with NTDs between January 1, 2014, and August 31, 2015, were eligible for this study. For those with a documented telephone number, follow-up phone surveys were conducted with the children's caregivers to assess mortality, morbidity, follow-up healthcare, and access to medical resources.RESULTS: Of the 201 patients, the vast majority (n = 185, 92%) were diagnosed with myelomeningocele. The median age at presentation was 6 days, the median length of stay was 20 days, and the median time to surgery was 10 days. Half of the patients had documented surgeries, with 5% receiving multiple procedures (n = 102, 51%): 80 defect closures (40%), 32 ventriculoperitoneal shunts (15%), and 1 endoscopic third ventriculostomy (0.5%). Phone surveys were completed for 53 patients with a median time to follow-up of 1.5 years. There were no statistically significant differences in demographics between the surveyed and nonrespondent groups. The 1-year mortality rate was 34% (n = 18). At the time of survey, 91% of the survivors (n = 30) have received healthcare since their initial discharge from MNRH, with 67% (n = 22) returning to MNRH. Hydrocephalus was diagnosed in 29 patients (88%). Caregivers reported physical deficits in 39% of patients (n = 13), clubfoot in 18% (n = 6), and bowel or bladder incontinence in 12% (n = 4). The surgical complication rate was 2.5%. Glasgow Outcome Scale-Extended pediatric revision scores were correlated with upper good recovery in 58% (n = 19) of patients, lower good recovery in 30% (n = 10), and moderate disability in 12% of patients (n = 4). Only 5 patients (15%) reported access to home health resources postdischarge.CONCLUSIONS: This study is the first to characterize the outcomes of children with NTDs that were treated at Uganda's national referral hospital. There is a great need for improved access to and coordination of care in antenatal, perioperative, and long-term settings to improve morbidity and mortality.

    View details for DOI 10.3171/2018.7.FOCUS18280

    View details for PubMedID 30269577

  • Mu and kappa opioids modulate mouse embryonic stem cell-derived neural progenitor differentiation via MAP kinases JOURNAL OF NEUROCHEMISTRY Hahn, J. W., Jagwani, S., Kim, E., Rendell, V. R., He, J., Ezerskiy, L. A., Wesselschmidt, R., Coscia, C. J., Belcheva, M. M. 2010; 112 (6): 1431-1441

    Abstract

    As embryonic stem cell-derived neural progenitors (NPs) have the potential to be used in cell replacement therapy, an understanding of the signaling mechanisms that regulate their terminal differentiation is imperative. In previous studies, we discovered the presence of functional mu opioid receptors (MOR) and kappa opioid receptors (KOR) in mouse embryonic stem cells and NPs. Here, MOR and KOR immunoreactivity was detected in NP-derived oligodendrocytes during three stages of their maturation in vitro. Moreover, we examined the modulation of retinoic acid-induced NP differentiation to astrocytes and neurons by mu, [D-ala(2), mephe(4), gly-ol(5)] enkephalin, or kappa, U69, 593, opioids. Both opioid agonists inhibited NP-derived neurogenesis and astrogenesis via their corresponding receptors as determined by immunocytochemistry. By administering selective inhibitors, we found that opioid inhibition of NP-derived astrogenesis was driven via extracellular-signal regulated kinase (ERK), while the p38 mitogen-activated protein kinase pathway was implicated in opioid attenuation of neurogenesis. In addition, mu and kappa opioids stimulated oligodendrogenesis from NP-derived NG2(+) oligodendrocyte progenitors via both ERK and p38 signaling pathways. Accordingly, both opioids induced ERK phosphorylation in NG2(+) cells. These results indicate that small molecules, such as MOR and KOR agonists may play a modulatory role in NP terminal differentiation.

    View details for DOI 10.1111/j.1471-4159.2009.06479.x

    View details for Web of Science ID 000274811500005

    View details for PubMedID 19895666

    View details for PubMedCentralID PMC2856797