All Publications

  • Purification and characterization of human neural stem and progenitor cells. Cell Liu, D. D., He, J. Q., Sinha, R., Eastman, A. E., Toland, A. M., Morri, M., Neff, N. F., Vogel, H., Uchida, N., Weissman, I. L. 2023; 186 (6): 1179

    Abstract

    The human brain undergoes rapid development at mid-gestation from a pool of neural stem and progenitor cells (NSPCs) that give rise to the neurons, oligodendrocytes, and astrocytes of the mature brain. Functional study of these cell types has been hampered by a lack of precise purification methods. We describe a method for prospectively isolating ten distinct NSPC types from the developing human brain using cell-surface markers. CD24-THY1-/lo cells were enriched for radial glia, which robustly engrafted and differentiated into all three neural lineages in the mouse brain. THY1hi cells marked unipotent oligodendrocyte precursors committed to an oligodendroglial fate, and CD24+THY1-/lo cells marked committed excitatory and inhibitory neuronal lineages. Notably, we identify and functionally characterize a transcriptomically distinct THY1hiEGFRhiPDGFRA- bipotent glial progenitor cell (GPC), which is lineage-restricted to astrocytes and oligodendrocytes, but not to neurons. Our study provides a framework for the functional study of distinct cell types in human neurodevelopment.

    View details for DOI 10.1016/j.cell.2023.02.017

    View details for PubMedID 36931245

  • Corrigendum: Revisiting Stem Cell-Based Clinical Trials for Ischemic Stroke. Frontiers in aging neuroscience He, J. Q., Sussman, E. S., Steinberg, G. K. 2022; 14: 875925

    Abstract

    [This corrects the article DOI: 10.3389/fnagi.2020.575990.].

    View details for DOI 10.3389/fnagi.2022.875925

    View details for PubMedID 35360207

  • A Clinical PET Imaging Tracer ([18F]DASA-23) to Monitor Pyruvate Kinase M2 Induced Glycolytic Reprogramming in Glioblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research Beinat, C., Patel, C. B., Haywood, T., Murty, S., Naya, L., Castillo, J. B., Reyes, S. T., Phillips, M., Buccino, P., Shen, B., Park, J. H., Koran, M. E., Alam, I. S., James, M. L., Holley, D., Halbert, K., Gandhi, H., He, J. Q., Granucci, M., Johnson, E., Liu, D. D., Uchida, N., Sinha, R., Chu, P., Born, D. E., Warnock, G. I., Weissman, I., Hayden Gephart, M., Khalighi, M. M., Massoud, T. F., Iagaru, A., Davidzon, G., Thomas, R., Nagpal, S., Recht, L. D., Gambhir, S. S. 2021

    Abstract

    PURPOSE: Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key process of cancer metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) cells with minimal expression in healthy brain. We describe the development, validation, and translation of a novel positron emission tomography (PET) tracer to study PKM2 in GBM. We evaluated 1-((2-fluoro-6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) in cell culture, mouse models of GBM, healthy human volunteers, and GBM patients.EXPERIMENTAL DESIGN: [18F]DASA-23 was synthesized with a molar activity of 100.47 {plus minus} 29.58 GBq/mol and radiochemical purity >95%. We performed initial testing of [18F]DASA-23 in GBM cell culture and human GBM xenografts implanted orthotopically into mice. Next we produced [18F]DASA-23 under FDA oversight, and evaluated it in healthy volunteers, and a pilot cohort of glioma patients.RESULTS: In mouse imaging studies, [18F]DASA-23 clearly delineated the U87 GBM from surrounding healthy brain tissue and had a tumor-to-brain ratio (TBR) of 3.6 {plus minus} 0.5. In human volunteers, [18F]DASA-23 crossed the intact blood-brain barrier and was rapidly cleared. In GBM patients, [18F]DASA-23 successfully outlined tumors visible on contrast-enhanced magnetic resonance imaging (MRI). The uptake of [18F]DASA-23 was markedly elevated in GBMs compared to normal brain, and it identified a metabolic non-responder within 1-week of treatment initiation.CONCLUSIONS: We developed and translated [18F]DASA-23 as a new tracer that demonstrated the visualization of aberrantly expressed PKM2 for the first time in human subjects. These results warrant further clinical evaluation of [18F]DASA-23 to assess its utility for imaging therapy-induced normalization of aberrant cancer metabolism.

    View details for DOI 10.1158/1078-0432.CCR-21-0544

    View details for PubMedID 34475101

  • CD47 blockade reduces the pathologic features of experimental cerebral malaria and promotes survival of hosts with Plasmodium infection. Proceedings of the National Academy of Sciences of the United States of America Torrez Dulgeroff, L. B., Oakley, M. S., Tal, M. C., Yiu, Y. Y., He, J. Q., Shoham, M., Majam, V., Okoth, W. A., Malla, P., Kumar, S., Weissman, I. L. 2021; 118 (11)

    Abstract

    CD47 is an antiphagocytic "don't eat me" signal that inhibits programmed cell removal of self. As red blood cells (RBCs) age they lose CD47 expression and become susceptible to programmed cell removal by macrophages. CD47-/- mice infected with Plasmodium yoelii, which exhibits an age-based preference for young RBCs, were previously demonstrated to be highly resistant to malaria infection. Our study sought to test the therapeutic benefit of CD47 blockade on ameliorating the clinical syndromes of experimental cerebral malaria (ECM), using the Plasmodium berghei ANKA (Pb-A) murine model. In vitro we tested the effect of anti-CD47 mAb on Plasmodium-infected RBC phagocytosis and found that anti-CD47 treatment significantly increased clearance of Plasmodium-infected RBCs. Infection of C57BL/6 mice with Pb-A is lethal and mice succumb to the clinical syndromes of CM between days 6 and 10 postinfection. Strikingly, treatment with anti-CD47 resulted in increased survival during the cerebral phase of Pb-A infection. Anti-CD47-treated mice had increased lymphocyte counts in the peripheral blood and increased circulating levels of IFN-γ, TNF-α, and IL-22. Despite increased circulating levels of inflammatory cytokines, anti-CD47-treated mice had reduced pathological features in the brain. Survival of ECM in anti-CD47-treated mice was correlated with reduced cellular accumulation in the cerebral vasculature, improved blood-brain barrier integrity, and reduced cytotoxic activity of infiltrating CD8+ T cells. These results demonstrate the therapeutic benefit of anti-CD47 to reduce morbidity in a lethal model of ECM, which may have implications for preventing mortality in young African children who are the highest casualties of CM.

    View details for DOI 10.1073/pnas.1907653118

    View details for PubMedID 33836556

    View details for PubMedCentralID PMC7980459

  • CD47 blockade reduces the pathologic features of experimental cerebral malaria and promotes survival of hosts with Plasmodium infection PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Dulgeroff, L., Oakley, M. S., Tal, M. C., Yiu, Y., He, J. Q., Shoham, M., Majam, V., Okoth, W. A., Malla, P., Kumar, S., Weissman, I. L. 2021; 118 (11)

    View details for DOI 10.1073/pnas.1907653118

    View details for Web of Science ID 000629635100001

  • Restoring metabolism of myeloid cells reverses cognitive decline in ageing. Nature Minhas, P. S., Latif-Hernandez, A., McReynolds, M. R., Durairaj, A. S., Wang, Q., Rubin, A., Joshi, A. U., He, J. Q., Gauba, E., Liu, L., Wang, C., Linde, M., Sugiura, Y., Moon, P. K., Majeti, R., Suematsu, M., Mochly-Rosen, D., Weissman, I. L., Longo, F. M., Rabinowitz, J. D., Andreasson, K. I. 2021

    Abstract

    Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty1-3. The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer's disease4-6. Systemically, circulating pro-inflammatory factors can promote cognitive decline7,8, and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration9,10. However, the underlying mechanisms that initiate and sustain maladaptive inflammation with ageing are not well defined. Here we show that in ageing mice myeloid cell bioenergetics are suppressed in response to increased signalling by the lipid messenger prostaglandin E2 (PGE2), a major modulator of inflammation11. In ageing macrophages and microglia, PGE2 signalling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flux and mitochondrial respiration. This energy-deficient state, which drives maladaptive pro-inflammatory responses, is further augmented by a dependence of aged myeloid cells on glucose as a principal fuel source. In aged mice, inhibition of myeloid EP2 signalling rejuvenates cellular bioenergetics, systemic and brain inflammatory states, hippocampal synaptic plasticity and spatial memory. Moreover, blockade of peripheral myeloid EP2 signalling is sufficient to restore cognition in aged mice. Our study suggests that cognitive ageing is not a static or irrevocable condition but can be reversed by reprogramming myeloid glucose metabolism to restore youthful immune functions.

    View details for DOI 10.1038/s41586-020-03160-0

    View details for PubMedID 33473210

  • Revisiting Stem Cell-Based Clinical Trials for Ischemic Stroke. Frontiers in aging neuroscience He, J. Q., Sussman, E. S., Steinberg, G. K. 2020; 12: 575990

    Abstract

    Stroke is the leading cause of serious long-term disability, significantly reducing mobility in almost half of the affected patients aged 65 years and older. There are currently no proven neurorestorative treatments for chronic stroke. To address the complex problem of restoring function in ischemic brain tissue, stem cell transplantation-based therapies have emerged as potential restorative therapies. Aligning with the major cell types found within the ischemic brain, stem-cell-based clinical trials for ischemic stroke have fallen under three broad cell lineages: hematopoietic, mesenchymal, and neural. In this review article, we will discuss the scientific rationale for transplanting cells from each of these lineages and provide an overview of published and ongoing trials using this framework.

    View details for DOI 10.3389/fnagi.2020.575990

    View details for PubMedID 33381020

    View details for PubMedCentralID PMC7767918

  • 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

  • Non-Contrast T2-Weighted MR Sequences for Long Term Monitoring of Asymptomatic Convexity Meningiomas. World neurosurgery He, J. Q., Iv, M. n., Li, G. n., Zhang, M. n., Hayden-Gephart, M. n. 2019

    Abstract

    Gadolinium based contrast agents (GBCA) used to enhance MRs have been linked to tissue deposition, including in the brain. The management of indolent tumors such as meningiomas requires frequent MRs to monitor for interval growth. Given concern regarding GBCA deposition, we sought to determine if non-contrast MRs in patients with asymptomatic meningiomas were equivalent to GBCA-enhanced MRs in surveillance monitoring.This IRB-approved retrospective chart review included 106 MR sequences from 18 patients. Inclusion criteria were adult patients with asymptomatic meningiomas who received baseline contrast-enhanced and non-contrast axial MR imaging of the brain. Exclusion criteria included: 1) baseline or follow-up axial images were not available for review 2) baseline scan was obtained without contrast 3) diagnosis of meningioma was uncertain. Percent tumor growth was measured by comparing cross-sectional area at maximum tumor diameter from the earliest and most recent scans. For each patient, change in tumor size over time was compared using T1+contrast, T2, and T2 FLAIR sequences. These were compared to a qualitative consensus reading by a neurosurgeon and a neuroradiologist.Measured change of greater than 10% was taken to represent tumor growth. In 17 out of 18 patients, measurement of non-contrast studies (T2 and T2 FLAIR) matched consensus. For one patient, imaging on T2 suggested 11% growth while T2 FLAIR and overall consensus was stability.Our study provides evidence that non-contrasted MR images are equivalent to contrast-weighted MRs to follow change in tumor size over time in asymptomatic meningiomas.

    View details for DOI 10.1016/j.wneu.2019.11.051

    View details for PubMedID 31734418

  • Pediatric High-Grade Glioma Glioblastoma: State-of-the-Art Clinical Neuroimaging He, J. Q., Whipple, N. S., Cheshier, S. H. 2019
  • 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 PubMedID 30269577

  • 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)

    View details for DOI 10.3171/2018.7.FOCUS18280

    View details for Web of Science ID 000446253400009

  • Introduction: Cancer Stem Cells CANCER STEM CELLS: TARGETING THE ROOTS OF CANCER, SEEDS OF METASTASIS, AND SOURCES OF THERAPY RESISTANCE Mitra, S. S., He, J. Q., Esparza, R., Hutter, G., Cheshier, S. H., Weissman, I., Liu, H., Lathia, J. D. 2016: 3–24

    View details for DOI 10.1016/B978-0-12-803892-5.00001-2

    View details for Web of Science ID 000403274400004

  • 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