Tonya Bliss

• Stanford University

Introduction: The cross-talk between the brain and peripheral immune organs plays a crucial role in the response to stroke injury. Spleen responses are implicated in stroke pathology and inflammatory responses. Hyperglycemia is known to worsen stroke outcomes, with increased immune cell infiltration into the brain. However, it remains unclear wheth...

Introduction: Intraparenchymal transplantation (tx) of human neural stem cells is in clinical trial for chronic ischemic stroke, but the mechanisms of action are unknown. Here we use longitudinal MR imaging and spatial transcriptomics in a rodent stroke model to investigate the regenerative responses of cell therapy on regional and molecular levels...

Introduction: Intraparenchymal stem cell transplantation shows therapeutic promise for chronic ischemic stroke patients. Our previous phase 1/2a trial revealed a transient T2-FLAIR (fluid-attenuated inversion recovery) MRI signal in the premotor cortex following intraparenchymal stem cell transplantation, the size of which positively correlated wit...

Introduction: Rat models are widely used in stroke research as they are well suited for behavior studies and brain imaging techniques. However, methods for studying immune responses and identifying distinct leukocyte subsets in rats lag behind mice in part due to lack of specific antibodies for flow cytometry. Several flow cytometry antibody panels...

Background: Acute hyperglycemia, which occurs in over 40% of ischemic stroke patients irrespective of pre-existing diabetes, exacerbates stroke injury. Understanding its mechanisms is vital for innovative treatments. Here we investigate the role of complement in hyperglycemia-exacerbated damage after stroke. Method: Male C57/BL6 mice (10-11 weeks)...

Introduction: Previous stroke studies in female rodents have demonstrated that the severity of ischemic damage is differentially impacted by the estrous cycle. Estrogen is considered to be neuroprotective, but it is unclear whether this protection is dependent on the vasodilator properties of estrogen. In this study, we investigated the impact of e...

Stem cell therapy shows promise for multiple disorders; however, the molecular crosstalk between grafted cells and host tissue is largely unknown. Here, we take a step toward addressing this question. Using translating ribosome affinity purification (TRAP) with sequencing tools, we simultaneously decode the transcriptomes of graft and host for huma...

Background: Acute hyperglycemia, which occurs in over 40% of ischemic stroke patients regardless of pre-existing diabetes, increases brain edema, hemorrhagic transformation (HT) and worsens stroke outcome. Understanding the mechanisms of hyperglycemia-exacerbated stroke injury will be vital for developing novel treatments. Here we identify systemic...

Background: Acute hyperglycemia occurs in over 40% of ischemic stroke patients, increases hemorrhagic transformation (HT) and worsens stroke outcome. Previous rodent studies reported deleterious effects of hyperglycemia on stroke outcome during acute stroke (within hours to days), however, its impact during subacute stroke period (days to weeks) re...

Background: Hyperglycemia occurs in over 40% of ischemic stroke patients, which induces hemorrhagic transformation (HT) and worsens stroke outcomes. The management of hyperglycemia with insulin did not show favorable outcomes. Thus, strategies for managing hyperglycemia-exacerbated stroke injury are urgently needed. We previously demonstrated that...

Stroke is a leading cause of long-term disability and death in the united states. The development of new therapies for stroke are sorely needed. There is great hope that stem cell therapy will create a paradigm shift in the treatment of stroke patients. A barrier to ensuring clinical success of stem cell therapy is the paucity of understanding of t...

Stroke is one of the major causes of chronic disability worldwide and increasing efforts have focused on studying brain repair and recovery after stroke. Following stroke, the primary injury site can disrupt functional connections in nearby and remotely connected brain regions, resulting in the development of secondary injuries that may impede long...

Stroke is the leading cause of adult disability in the United States. Because post-stroke inflammation is a critical determinant of damage and recovery after stroke, understanding the interplay between the immune system and the brain after stroke holds much promise for therapeutic intervention. An understudied, but important aspect of this interpla...

Identifying the secretome of grafted stem cells is an important first step to elucidate how the graft communicates with the host brain, at the molecular level , to enhance post-stroke recovery. Here we use Translating Ribosome Affinity Purification (TRAP) to uncover the secretome of grafted human neural stem cells (hNSCs) and identify potential eff...

Human neural stem cell (hNSC) transplantation improves recovery in preclinical stroke models. However their effects on surviving sensorimotor circuits are not well understood. Here we performed a comprehensive electrophysiological assessment and RNA-seq analysis of the stroke-injured rat cortex after transplantation of two hNSC lines, G010 (fetal-d...

Magnetic particle imaging is an emerging tomographic technique with the potential for simultaneous high-resolution, high-sensitivity, and real-time imaging. Magnetic particle imaging is based on the unique behavior of superparamagnetic iron oxide nanoparticles modeled by the Langevin theory, with the ability to track and quantify nanoparticle conce...

Currently, no medical therapies exist to augment stroke recovery. Stem cells are an intriguing treatment option being evaluated, but cell-based therapies have several challenges including developing a stable cell product with long term reproducibility. Since much of the improvement observed from cellular therapeutics is believed to result from trop...

Exogenous human neural progenitor cells (hNPCs) are promising stroke therapeutics, but optimal delivery conditions and exact recovery mechanisms remain elusive. To further elucidate repair processes and improve stroke outcomes, we developed an electrically conductive, polymer scaffold for hNPC delivery. Electrical stimulation of hNPCs alters their...

Stem cell therapies can promote neural repair and regeneration, yet controversy regarding optimal cell source and mechanism of action has slowed clinical translation, potentially due to undefined cellular heterogeneity. Single-cell resolution is needed to identify clinically relevant subpopulations with the highest therapeutic relevance. We combine...

List of hBM-MSC and hNSC cluster defining genes determined via Kolmogorov–Smirnov testing from Figures 1 and 2. Bold genes encode cell surface markers.

Introduction: Neural stem cell (NSC) transplantation is being explored as a potential therapy for ischemic stroke (IS). Although research has shown the efficacy of NSCs in IS, little is known about the gene expression profile of the NSCs after transplantation. To date this has been challenging due to the issue of trying to distinguish factors expre...

View largeDownload slide While tonic GABA appears to suppress brain repair after stroke, the effects of phasic (synaptic) GABA signalling are unclear. Hiu et al. reveal an increase in phasic GABA signalling during the repair phase that enhances plasticity-related recovery in mice. Increasing phasic signalling with zolpidem improves behavioural rec...

Stem cell transplantation has emerged as a promising new experimental treatment for stroke; understanding its mechanism of action will facilitate the translation of stem cell therapy to the clinic. The ultimate change in brain plasticity is manifested at the synaptic level, however, the synaptic remodeling after stem cell therapy remains unknown. V...

Stem cell therapy is a promising treatment strategy for stroke that has been shown to improve functional recovery in preclinical stroke models and is currently being investigated in clinical trials. In this chapter, we review the development of intracerebral (IC) transplantation as a strategy for targeted cell delivery to the stroke-injured brain,...

Background: Neural stem cells (NSCs) improve functional recovery after stroke, but the optimal method and conditions for delivery remain elusive. Tissue engineered scaffolds offer a unique method to manipulate and improve NSC function. We have developed a novel NSC delivery system utilizing an electrically conductive polymer scaffold to improve rec...

Stroke is the leading cause of adult disability and the fourth most common cause of death in the United States. Inflammation is thought to play an important role in stroke pathology, but the factors that promote inflammation in this setting remain to be fully defined. An understudied but important factor is the role of meningeal-located immune cell...

Background: Stem cell transplantation (Tx) has emerged as a promising new experimental treatment for stroke; understanding its mechanism of action will facilitate the translation of stem cell therapy to the clinic. The ultimate change in brain plasticity is manifested at the synaptic level, however, the synaptic remodeling after stem cell therapy r...

Background: Stroke is a major cause of disability yet pharmacotherapy targeting the recovery phase is lacking. Cortical circuit reorganization adjacent to the stroke site promotes recovery, thus elucidating mechanisms that promote this plasticity could lead to new therapeutics. Tonic neuronal inhibition, mediated by extrasynaptic GABA A receptors,i...

Background: Inflammation critically contributes to post-stroke brain damage and consequently there is much interest in factors that influence stroke-induced brain inflammation. Interleukin 6 (IL-6) has been heralded as an important predictor of stroke outcome, however there are conflicting reports describing detrimental, beneficial and even no effe...

Conventional therapeutic strategies in stroke, both ischemic and hemorrhagic, have focused on the prevention of further stroke. Stem cell transplantation shifts the paradigm of stroke therapy in that it aims to repair the ischemic brain by facilitating the brain’s plasticity to regenerate synaptic structures and reorganize its functional architectu...

INTRODUCTION: Bone morphogenetic protein(BMP)-2 has been shown to be a potent enhancer of spine fusion but its role in osteoporosis has not yet been defined. The number of vertebral compression fractures related to osteoporosis is expected to double by 2025.(1) BMP-2 responsiveness has recently been shown to be enhanced by an intracellular protein,...

Introduction: Stem cell transplantation has emerged as a promising new experimental treatment for stroke; understanding its mechanism of action will facilitate the translation of stem cell therapy to the clinic. Previous work from our lab and others suggests that transplanted stem cells function by enhancing endogenous brain repair processes includ...

Inflammation critically contributes to post-stroke brain damage. Mast cells (MCs), perivascular cells best known as effector cells involved in the development of inflammatory processes, have been reported to exacerbate stroke pathology. Unlike other immune cells, mature MCs do not circulate but are resident in virtually all anatomical sites, includ...

Background Post-ischemic inflammation plays an important role in stroke pathology. Understanding the details and mechanisms of post-stroke inflammation is essential to develop therapeutics that can reduce the damage and promote recovery. Macrophages are known to promote both injury and repair in various pathologies, and these divergent properties m...

Introduction: The mechanisms of functional recovery after stroke are thought to be based on structural and functional changes in brain circuits adjacent to or connected with the stroke site. Deciphering these changes at the synaptic level is key to understanding the re-organization of the synaptic circuitry. Here we use a combined approach of i) ar...

Introduction: The mechanisms of functional recovery after stroke are thought to be based on structural and functional changes in brain circuits adjacent to or connected with the stroke site. Deciphering these changes at the synaptic level is key to understanding the re-organization of the synaptic circuitry (i.e. the connectome). Quantitative infor...

Stem cell transplantation promises new hope for the treatment of stroke although significant questions remain about how the grafted cells elicit their effects. One hypothesis is that transplanted stem cells enhance endogenous repair mechanisms activated after cerebral ischaemia. Recognizing that bilateral reorganization of surviving circuits is ass...

Middle cerebral artery occlusion (MCAO) in rats is a well-studied experimental model for ischemic stroke leading to brain infarction and functional deficits. Many preclinical studies have focused on a small time window after the ischemic episode to evaluate functional outcome for screening therapeutic candidates. Short evaluation periods following...

Cell transplantation offers a novel therapeutic strategy for stroke; however, how transplanted cells function in vivo is poorly understood. We show for the first time that after subacute transplantation into the ischemic brain of human central nervous system stem cells grown as neurospheres (hCNS-SCns), the stem cell-secreted factor, human vascular...

Background / Purpose: The study aimed to look at what changes the transplanted stem cells induced in the rodent brain after stroke with the ultimate goal of understanding how transplanted stem cells enhance functional recovery after stroke.Stem cells act by secreting factors that enhance endogenous repair mechanisms that occur naturally after str...

Stem cell transplantation has evolved as a promising experimental treatment approach for stroke. In this review, we address the major hurdles for successful translation from basic research into clinical applications and discuss possible strategies to overcome these issues. We summarize the results from present pre-clinical and clinical studies and...

A consortium of translational stem cell and stroke experts from multiple academic institutes and biotechnology companies, under the guidance of the government (FDA/NIH), is missing. Here, we build a case for the establishment of this consortium if cell therapy for stroke is to advance from the laboratory to the clinic.

Vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) play important roles during neurovascular repair after stroke. In this study, we imaged VEGFR expression with positron emission tomography (PET) to noninvasively analyze poststroke angiogenesis. Female Sprague-Dawley rats after distal middle cerebral artery occlusion surgery were...

Thrombospondins 1 and 2 (TSP-1/2) belong to a family of extracellular glycoproteins with angiostatic and synaptogenic properties. Although TSP-1/2 have been postulated to drive the resolution of postischemic angiogenesis, their role in synaptic and functional recovery is unknown. We investigated whether TSP-1/2 are necessary for synaptic and motor...

Intracerebral injection of the vasoconstrictor peptide, endothelin-1 (ET-1), has been used as a method to induce focal ischemia in rats. The relative technical simplicity of this model makes it attractive for use in mice. However, the effect of ET-1 on mouse brains has not been firmly established. In this study, we determined the ability of ET-1 to...

Endogenous neural stem cells normally reside in their niche, the subventricular zone, in the uninjured rodent brain. Upon stroke, these cells become more proliferative and migrate away from the subventricular zone into the surrounding parenchyma. It is not known whether this stroke-induced behavior is due to changes in the niche or introduction of...

Noninvasive monitoring of stem cells, using high-resolution molecular imaging, will be instrumental to improve clinical neural transplantation strategies. We show that labeling of human central nervous system stem cells grown as neurospheres with magnetic nanoparticles does not adversely affect survival, migration, and differentiation or alter neur...

No treatment currently exists to restore lost neurological function after stroke. A growing number of studies highlight the potential of stem cell transplantation as a novel therapeutic approach for stroke. In this review we summarize these studies, discuss potential mechanisms of action of the transplanted cells, and emphasize the need to determin...

Cell transplantation offers a potential new treatment for stroke. Animal studies using models that produce ischemic damage in both the striatum and the frontal cortex have shown beneficial effects when hNT cells (postmitotic immature neurons) were transplanted into the ischemic striatum. In this study, we investigated the effect of hNT cells in a m...

We characterize the survival, migration, and differentiation of human neurospheres derived from CNS stem cells transplanted into the ischemic cortex of rats 7 days after distal middle cerebral artery occlusion. Transplanted neurospheres survived robustly in naive and ischemic brains 4 wk posttransplant. Survival was influenced by proximity of the g...

Increasing evidence suggests that glutamate activates the generation of lactate from glucose in astrocytes; this lactate is shuttled to neurons that use it as a preferential energy source. We explore this multicellular "lactate shuttle" with a novel dual-cell, dual-gene therapy approach and determine the neuroprotective potential of enhancing this...

There is an increasing recognition of the damaging role played by oxygen radicals in mediating necrotic neuronal injury. As such, it becomes important to understand the transport mechanisms that help maintain appropriate levels of small molecule antioxidants such as ascorbate in the brain. It has long been known that the transport of dehydroascorba...

There have been a number of studies that have examined the potential benefits of companies investing in corporate fitness (CF) programmes and the results have been well publicized. However little research has investigated the perceptions of corporate employees. This study explores employee perceptions of CF and highlights the management implication...

Glucose is the major energy source during normal adult brain activity. However, it appears that glial-derived lactate is preferred as an energy substrate by neurons following hypoxia-ischemia. We examined factors influencing this switch in energetic bias from glucose to lactate in cultured hippocampal neurons, focusing on the effects of the physiol...

Glucocorticoids (GCs), the adrenal steroids released during stress, can compromise the ability of hippocampal neurons to survive necrotic neurological insults. This GC-induced endangerment has energetic facets, in that it can be attenuated with energy supplementation. In the present report, we studied the effects of GCs on the metabolic response of...

The determination of neurotoxicity in monolayer mixed cultures has traditionally necessitated the time consuming and subjective procedure of counting neurons. In this paper, we propose a modification of an immunohistochemical staining method with a neuron-specific antibody against MAP2, that allows for quantification of neuron number to be done usi...

DNA-dependent protein kinase (DNA-PK), which is involved in DNA double-strand break repair and V(D)J recombination, is comprised of a DNA-targeting component termed Ku and an approximately 465-kD catalytic subunit, DNA-PKcs. Although DNA-PK phosphorylates proteins in the presence of DSBs or other discontinuities in the DNA double helix in vitro, th...

Double strand break repair and V(D)J recombination in mammalian cells require the function of the Ku protein complex and the DNA-dependent protein kinase. The DNA-dependent protein kinase is targeted to DNA through its interaction with the Ku protein complex, and thus the specificity of template recognition in the repair and recombination reactions...

The insulin-like effects of various vanadium compounds (orthovanadate, vanadyl and peroxides of vanadate) on rates of glucose oxidation, lactate formation and glycogen synthesis were measured in isolated incubated epitrochlearis (mainly type II fibres) and soleus (mainly type I fibres) muscle preparations. There was a small stimulation of the rate...