Haojun Lucy Xu

All Publications

• Elevated hematopoietic stem cell frequency in mouse alveolar bone marrow. Stem cell reports Niizuma, K., Morikawa, S., Gars, E., Xiang, J., Matsubara-Takahashi, T., Saito, R., Takematsu, E., Wang, Y., Xu, H., Wakimoto, A., Tan, T. K., Kubota, Y., Chan, C. K., Weissman, I. L., Nakagawa, T., Wilkinson, A. C., Nakauchi, H., Yamamoto, R. 2024: 102374

  Abstract

  Hematopoietic stem cells (HSCs) are crucial for maintaining hematopoietic homeostasis and are localized within distinct bone marrow (BM) niches. While BM niches are often considered similar across different skeletal sites, we discovered that the alveolar BM (al-BM) in the mandible harbors the highest frequency of immunophenotypic HSCs in nine different skeletal sites. Transplantation assays revealed significantly increased engraftment from al-BM compared to femur, tibia, or pelvis BM, likely due to a higher proportion of alveolar HSCs. Moreover, hematopoietic progenitor cells (c-Kit+ Sca-1+ Lin-) in al-BM exhibited increased quiescence and reduced apoptosis, indicating superior maintenance and survival characteristics. We also observed an enrichment of mesenchymal stromal cells and skeletal stem cells in al-BM, suggesting a more supportive microenvironment. These findings indicate that al-BM provides a unique microenvironment conducive to higher frequency of HSCs, offering new insights into site-specific hematopoiesis.

  View details for DOI 10.1016/j.stemcr.2024.11.004

  View details for PubMedID 39672154

• Nf1 mutation disrupts activity-dependent oligodendroglial plasticity and motor learning in mice. Nature neuroscience Pan, Y., Hysinger, J. D., Yalçın, B., Lennon, J. J., Byun, Y. G., Raghavan, P., Schindler, N. F., Anastasaki, C., Chatterjee, J., Ni, L., Xu, H., Malacon, K., Jahan, S. M., Ivec, A. E., Aghoghovwia, B. E., Mount, C. W., Nagaraja, S., Scheaffer, S., Attardi, L. D., Gutmann, D. H., Monje, M. 2024

  Abstract

  Neurogenetic disorders, such as neurofibromatosis type 1 (NF1), can cause cognitive and motor impairments, traditionally attributed to intrinsic neuronal defects such as disruption of synaptic function. Activity-regulated oligodendroglial plasticity also contributes to cognitive and motor functions by tuning neural circuit dynamics. However, the relevance of oligodendroglial plasticity to neurological dysfunction in NF1 is unclear. Here we explore the contribution of oligodendrocyte progenitor cells (OPCs) to pathological features of the NF1 syndrome in mice. Both male and female littermates (4-24 weeks of age) were used equally in this study. We demonstrate that mice with global or OPC-specific Nf1 heterozygosity exhibit defects in activity-dependent oligodendrogenesis and harbor focal OPC hyperdensities with disrupted homeostatic OPC territorial boundaries. These OPC hyperdensities develop in a cell-intrinsic Nf1 mutation-specific manner due to differential PI3K/AKT activation. OPC-specific Nf1 loss impairs oligodendroglial differentiation and abrogates the normal oligodendroglial response to neuronal activity, leading to impaired motor learning performance. Collectively, these findings show that Nf1 mutation delays oligodendroglial development and disrupts activity-dependent OPC function essential for normal motor learning in mice.

  View details for DOI 10.1038/s41593-024-01654-y

  View details for PubMedID 38816530

  View details for PubMedCentralID 3842597

• Immunotherapy-related cognitive impairment after CAR T cell therapy in mice. bioRxiv : the preprint server for biology Geraghty, A. C., Acosta-Alvarez, L., Rotiroti, M., Dutton, S., O'Dea, M. R., Woo, P. J., Xu, H., Shamardani, K., Mancusi, R., Ni, L., Mulinyawe, S. B., Kim, W. J., Liddelow, S. A., Majzner, R. G., Monje, M. 2024

  Abstract

  Persistent central nervous system (CNS) immune dysregulation and consequent dysfunction of multiple neural cell types is central to the neurobiological underpinnings of a cognitive impairment syndrome that can occur following traditional cancer therapies or certain infections. Immunotherapies have revolutionized cancer care for many tumor types, but the potential long-term cognitive sequelae are incompletely understood. Here, we demonstrate in mouse models that chimeric antigen receptor (CAR) T cell therapy for both CNS and non-CNS cancers can impair cognitive function and induce a persistent CNS immune response characterized by white matter microglial reactivity and elevated cerebrospinal fluid (CSF) cytokines and chemokines. Consequently, oligodendroglial homeostasis and hippocampal neurogenesis are disrupted. Microglial depletion rescues oligodendroglial deficits and cognitive performance in a behavioral test of attention and short-term memory function. Taken together, these findings illustrate similar mechanisms underlying immunotherapy-related cognitive impairment (IRCI) and cognitive impairment following traditional cancer therapies and other immune challenges.

  View details for DOI 10.1101/2024.05.14.594163

  View details for PubMedID 38798554

  View details for PubMedCentralID PMC11118392

• Adaptive and maladaptive myelination in health and disease. Nature reviews. Neurology Knowles, J. K., Batra, A., Xu, H., Monje, M. 2022

  Abstract

  Within the past decade, multiple lines of evidence have converged to identify a critical role for activity-regulated myelination in tuning the function of neural networks. In this Review, we provide an overview of accumulating evidence that activity-regulated myelination is required for brain adaptation and learning across multiple domains. We then discuss dysregulation of activity-dependent myelination in the context of neurological disease, a novel frontier with the potential to uncover new mechanisms of disease pathogenesis and to develop new therapeutic strategies. Alterations in myelination and neural network function can result from deficient myelin plasticity that impairs neurological function or from maladaptive myelination, in which intact activity-dependent myelination contributes to the disease process by promoting pathological patterns of neuronal activity. These emerging mechanisms suggest new avenues for therapeutic intervention that could more fully address the complex interactions between neurons and oligodendroglia.

  View details for DOI 10.1038/s41582-022-00737-3

  View details for PubMedID 36376595

• Maladaptive myelination promotes generalized epilepsy progression. Nature neuroscience Knowles, J. K., Xu, H., Soane, C., Batra, A., Saucedo, T., Frost, E., Tam, L. T., Fraga, D., Ni, L., Villar, K., Talmi, S., Huguenard, J. R., Monje, M. 2022

  Abstract

  Activity-dependent myelination can fine-tune neural network dynamics. Conversely, aberrant neuronal activity, as occurs in disorders of recurrent seizures (epilepsy), could promote maladaptive myelination, contributing to pathogenesis. In this study, we tested the hypothesis that activity-dependent myelination resulting from absence seizures, which manifest as frequent behavioral arrests with generalized electroencephalography (EEG) spike-wave discharges, promote thalamocortical network hypersynchrony and contribute to epilepsy progression. We found increased oligodendrogenesis and myelination specifically within the seizure network in two models of generalized epilepsy with absence seizures (Wag/Rij rats and Scn8a+/mut mice), evident only after epilepsy onset. Aberrant myelination was prevented by pharmacological seizure inhibition in Wag/Rij rats. Blocking activity-dependent myelination decreased seizure burden over time and reduced ictal synchrony as assessed by EEG coherence. These findings indicate that activity-dependent myelination driven by absence seizures contributes to epilepsy progression; maladaptive myelination may be pathogenic in some forms of epilepsy and other neurological diseases.

  View details for DOI 10.1038/s41593-022-01052-2

  View details for PubMedID 35501379

• Sufficiency for inducible Caspase-9 safety switch in human pluripotent stem cells and disease cells. Gene therapy Nishimura, T., Xu, H., Iwasaki, M., Karigane, D., Saavedra, B., Takahashi, Y., Suchy, F. P., Monobe, S., Martin, R. M., Ohtaka, M., Nakanishi, M., Burrows, S. R., Cleary, M. L., Majeti, R., Shibuya, A., Nakauchi, H. 2020

  Abstract

  Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have promising potential for opening new avenues in regenerative medicine. However, since the tumorigenic potential of undifferentiated pluripotent stem cells (PSCs) is a major safety concern for clinical transplantation, inducible Caspase-9 (iC9) is under consideration for use as a fail-safe system. Here, we used targeted gene editing to introduce the iC9 system into human iPSCs, and then interrogated the efficiency of inducible apoptosis with normal iPSCs as well as diseased iPSCs derived from patients with acute myeloid leukemia (AML-iPSCs). The iC9 system induced quick and efficient apoptosis to iPSCs in vitro. More importantly, complete eradication of malignant cells without AML recurrence was shown in disease mouse models by using AML-iPSCs. In parallel, it shed light on several limitations of the iC9 system usage. Our results suggest that careful use of the iC9 system will serve as an important countermeasure against posttransplantation adverse events in stem cell transplantation therapies.

  View details for DOI 10.1038/s41434-020-0179-z

  View details for PubMedID 32704085

• Inhibition of ice nucleation by slippery liquid-infused porous surfaces (SLIPS) PHYSICAL CHEMISTRY CHEMICAL PHYSICS Wilson, P. W., Lu, W., Xu, H., Kim, P., Kreder, M. J., Alvarenga, J., Aizenberg, J. 2013; 15 (2): 581-585

  Abstract

  Ice repellent coatings have been studied and keenly sought after for many years, where any advances in the durability of such coatings will result in huge energy savings across many fields. Progress in creating anti-ice and anti-frost surfaces has been particularly rapid since the discovery and development of slippery, liquid infused porous surfaces (SLIPS). Here we use SLIPS-coated differential scanning calorimeter (DSC) pans to investigate the effects of the surface modification on the nucleation of supercooled water. This investigation is inherently different from previous studies which looked at the adhesion of ice to SLIPS surfaces, or the formation of ice under high humidity conditions. Given the stochastic nature of nucleation of ice from supercooled water, multiple runs on the same sample are needed to determine if a given surface coating has a real and statistically significant effect on the nucleation temperature. We have cycled supercooling to freezing and then thawing of deionized water in hydrophilic (untreated aluminum), hydrophobic, superhydrophobic, and SLIPS-treated DSC pans multiple times to determine the effects of surface treatment on the nucleation and subsequent growth of ice. We find that SLIPS coatings lower the nucleation temperature of supercooled water in contact with statistical significance and show no deterioration or change in the coating performance even after 150 freeze-thaw cycles.

  View details for DOI 10.1039/c2cp43586a

  View details for Web of Science ID 000311963600023

  View details for PubMedID 23183624