Laura Goldberg

STRM.BIO

Extracellular vesicles (EVs) are critical mediators of intercellular communication within the bone marrow niche and have been implicated in numerous features of aging. However, their role in natural hematopoietic stem cell (HSC) aging has not been fully elucidated. The goal of this work was to test the hypothesis that EVs from whole bone marrow (BM...

Studies in hematopoietic aging have shown that classically defined, highly purified hematopoietic stem cells (HSCs) increase in number but have impaired function and exhibit myeloid skewing. However, we identified a cycling population of HSCs in young mice that appear to be preferentially lost during standard HSC isolations and therefore poorly rep...

At present, there is no reliable biomarker for the diagnosis of traumatic brain injury (TBI). Studies have shown that extracellular vesicles released by damaged cells into biological fluids can be used as potential biomarkers for diagnosis of TBI and evaluation of TBI severity. We hypothesize that the genetic profile of salivary extracellular vesic...

The underlying mechanism of normal lung organogenesis is not well understood. An increasing number of studies are demonstrating that extracellular vesicles (EVs) play critical roles in organ development by delivering microRNAs (miRNA) to neighboring and distant cells. miRNAs are important for fetal lung growth; however, the role of miRNA–EVs (miRNA...

When studying purified hematopoietic stem cells, the urge for mechanisms and reductionist approaches appears to be overwhelming. The prime focus of the field has recently been on the study of highly purified hematopoietic stem cells using various lineage and stem cell-specific markers, all of which adequately and conveniently fit the established hi...

Rationale: Mesenchymal stem cell extracellular vesicles attenuate pulmonary hypertension, but their ability to reverse established disease in larger animal models and the duration and mechanism(s) of their effect is unknown. Objectives: Determine the efficacy and mechanism of mesenchymal stem cells extracellular vesicles on attenuating pulmonary...

Aging is accompanied by loss of tissue homeostasis, deterioration in organ function and an increased incidence of disease. Age-related changes in the adult stem/progenitor compartment likely drive much of this aging phenotype. For the hematopoietic system, it has been shown that the number of hematopoietic stem cells (HSCs) increases with age, but...

We have previously shown that injury induced by irradiation to murine marrow can be partially or completely reversed by exposure to human or murine mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs). Investigation of the biodistribution of EVs in vivo is essential for understanding EV biology. In this study, we evaluated the DiD lipid...

Pulmonary hypertension (PH) is an incurable disease characterized by pulmonary vascular remodeling and ultimately death. Two rodent models of PH include treatment with monocrotaline or exposure to a vascular endothelial growth factor receptor inhibitor and hypoxia. Studies in these models indicated that damaged lung cells evolve extracellular vesic...

Traumatic brain injury (TBI) is a common cause of death and acquired disability in adults and children. Identifying biomarkers for mild TBI (mTBI) that can predict functional impairments on neuropsychiatric and neurocognitive testing after head trauma is yet to be firmly established. Extracellular vesicles (EVs) are known to traffic from the brain...

Background Extracellular Vesicles (EVs) compose a naturally occurring, heterogeneous group of membrane-bound, nano-sized particles shed by all cells. Depending on cellular type, physiological state, and mode of secretion some harbor potent regenerative properties while others have the propensity to induce disease. Human bone marrow mesenchymal stem...

Extracellular vesicles (EVs) including exosomes and microvesicles, have been found to deliver both mRNA and transcriptional modulators to target cells and affect their phenotype. Vesicles derived from mesenchymal stem cells (MSC) have been shown to affect the phenotype and induce healing of many different cell types. Our recent published work has s...

Introduction Extracellular vesicles (EVs) form a unique class of messengers for intercellular communication. Depending on their cell of origin, EVs have the ability to induce a phenotypic change in the recipient cell. For example, EVs from explant prostate cancer induce a neoplastic phenotype in normal prostate cell lines. Conversely, EVs from huma...

Extracellular vesicles (EVs) are important mediators of intercellular communication and have been implicated in myriad physiologic and pathologic processes within the hematopoietic system. Numerous factors influence the ability of EVs to communicate with target marrow cells, but little is known about how circadian oscillations alter EV function. In...

Hematopoietic stem cell biology has focused on stem cell purification and the definition of the regulation of purified stem cells in a hierarchical system. Work on the whole unpurified murine marrow cell population has indicated that a significant number of hematopoietic stem cells, rather than being dormant, are actively cycling, always changing p...

Aims: The pathogenic mechanisms of pulmonary arterial hypertension (PAH) remain unclear, but involve dysfunctional endothelial cells (ECs), dysregulated immunity and inflammation in the lung. We hypothesize that a developmental process called endothelial to haematopoietic transition (EHT) contributes to the pathogenesis of pulmonary hypertension (...

Purpose of Review Our understanding of the biology of hematopoietic stem cells is evolving beyond hierarchical models and markers of stem cell purification to a far more fluid model wherein degrees of multipotency of individual cells can change over time. This review is to outline these new concepts: Recent Findings The long-term repopulating hema...

Purpose of Review This report defines new concepts of hematopoietic stem cell biology. Recent Findings We have utilized three different approaches which show that long-term repopulating hematopoietic stem cells are actively cycling and always changing phenotype. In addition, this is reversible. This indicates that the stem cell cannot be purified...

The adult marrow hematopoietic stem cell biology has largely been based on studies of highly purified stem cells. This is unfortunate because during the stem cell purification the great bulk of stem cells are discarded. These cells are actively proliferating. The final purified stem cell is dormant and not representative of the whole stem cell comp...

The role of bone marrow (BM) cells in modulating pulmonary hypertensive responses is not well understood. Determine if BM-derived endothelial progenitor cells (EPCs) induce pulmonary hypertension (PH) and if this is attenuated by mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs). Three BM populations were studied: (a) BM from vehicle...

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Mesenchymal stromal cells (MSC) have been shown to reverse radiation damage to marrow stem cells. We have evaluated the capacity of MSC-derived extracellular vesicles (MSC-EVs) to mitigate radiation injury to marrow stem cells at 4 h to 7 days after irradiation. Significant restoration of marrow stem cell engraftment at 4, 24 and 168 h post-irradia...

Aims Extracellular vesicles (EVs) from mice with monocrotaline (MCT)-induced pulmonary hypertension (PH) induce PH in healthy mice and the exosomes (EXO) fraction of EVs from mesenchymal stem cells (MSCs) can blunt the development of hypoxic PH. We sought to determine if the EXO fraction of EVs is responsible for modulating pulmonary vascular respo...

Rationale: We have demonstrated that whole, undifferentiated bone marrow (WBM) cells isolated from mice with monocrotaline (MCT)-induced pulmonary hypertension (PH) cause pulmonary hypertensive changes when transplanted into lethally-irradiated mice (Aliotta et al., 2014 ATS abstract). In addition, mesenchymal stem cell (MSC)-derived extracellular...

Background: Hematopoietic stem cells (HSCs) have tremendous self-renewal and differentiation capacity. The majority of murine hematopoietic stem cell studies have focused on rare purified populations of HSCs, conventionally described as negative for lineage-specific markers and positive for particular cell surface epitope profiles, including c-Kit,...

We have shown that Human or mouse mesenchymal stem cell (MSC) derived vesicles separated by differential centrifugation (300g, 10kg &100kg) can reverse radiation whole bone marrow (WBM) damage in vitro on the hematopoietic cell line FDC-P1 and in vivo on recovery of stem cells and differentiated blood cells after whole body irradiation. The vesicle...

Background: Our group has previously demonstrated that murine whole bone marrow cells (WBM) that internalize lung-derived extracellular vesicles (LDEVs) in culture express pulmonary epithelial cell-specific genes for up to 12 weeks. In addition, the lungs of lethally irradiated mice transplanted with lung vesicle-modulated marrow have 5 times more...

The NIH Extracellular RNA Communication Program's initiative on clinical utility of extracellular RNAs and therapeutic agents and developing scalable technologies is reviewed here. Background information and details of the projects are presented. The work has focused on modulation of target cell fate by extracellular vesicles (EVs) and RNA. Work on...

Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.

The field of hematopoietic stem cell biology has become increasingly dominated by the pursuit and study of highly purified populations of hematopoietic stem cells (HSCs). Such HSCs are typically isolated based on their cell surface marker expression patterns and ultimately defined by their multipotency and capacity for self-generation. However, eve...

The study of highly purified hematopoietic stem cells (HSCs) has dominated the field of hematopoietic stem cell biology. It is widely believed that the true stem cell population lies within the Lineage negative (Lin-) population, further sub-fractionated using positive and negative selection for surface markers such as c-Kit, Sca-1, CD150, CD41, CD...

Introduction: Extracellular vesicles (EVs) are membrane-bound, subcellular fragments that contain DNA, RNA, protein and lipids, and play an important role in intercellular communication. They have been implicated in myriad physiologic and pathologic processes within the hematopoietic system including thrombosis and leukemia, and as such, have treme...

Keywords: extracellular vesicles; stem cells heterogeneity; cycling stem cell

Several decades of research in the hematopoietic stem cell (HSC) field have led to increasingly detailed characterizations of HSC phenotype, HSC niches, and the molecular pathways governing stem cell self-renewal and differentiation fate. One of the unifying principles of virtually all studies to date has been the focus on highly purified stem cell...

Marrow cells are a rich source of vesicles (released from their surface or endosomal compartment that may deliver proteins, ribonucleic acid (RNA), and microRNA (miRNA) into damaged organs. Based on this, paracrine effects probably make major contributions in most of the currently reported positive results in clinical trials employing adult hematop...

Current concepts of hematopoiesis are encompassed in a hierarchical stem cell model. This developed initially from studies of colony-forming unit spleen (CFU-S) and in-vitro progenitors for different cell lineages, but then evolved into a comprehensive model of cells with different in vivo differentiative and proliferative potential. These cells we...

Early work on platelet and erythrocyte vesicles interpreted the phenomena as a discard of material from cells. Subsequently vesicles were studied as possible vaccines and most recently there has been a focus on the effects of vesicles on cell fate. Recent studies have indicated that extracellular vesicles, previously referred to as microvesicles or...

Chronic myelogenous leukemia (CML) is a disease in which a small number of primitive renewing stem cells give rise to more differentiated hematopoietic cells. The stem cells are the basis for continuation and recurrence of the disease. Recent reports have suggested that most cancers are driven by rare stem cells which may have a different sensitivi...

Extracellular vesicles, including exosomes and microvesicles, have been shown to epigenetically modulate cell fate (Aliotta et al JEV, 2013). We have evaluated the effect of murine or human mesenchymal stem cell (MSC)-derived vesicles on marrow from irradiated mice or on the marrow cell line, FDC-P1, irradiated in vitro. B6.SJL mice were exposed to...

Prevailing wisdom holds that hematopoietic stem cells (HSCs) are predominantly quiescent. Although HSC cycle status has long been the subject of scrutiny, virtually all marrow stem cell research has been based on studies of highly purified HSCs. Here we explored the cell cycle status of marrow stem cells in un-separated whole bone marrow (WBM). We...

2308 Hematopoietic stem cell biologists have amassed a tremendous depth of knowledge about the biology of the marrow stem cell over the past few decades, facilitating invaluable basic scientific and translational advances in the field. Most of the studies to date have focused on highly purified populations of marrow cells, with emphasis placed on t...

Long-term hematopoietic stem cells (LT-HSC) and short-term hematopoietic stem cells (ST-HSC) have been characterized as having markedly different in vivo repopulation, but similar in vitro growth in liquid culture. These differences could be due to differences in marrow homing. We evaluated this by comparing results when purified ST-HSC and LT-HSC...

We have shown that hematopoietic stem/progenitor cell phenotype and differentiative potential change throughout cell cycle. Lung-derived microvesicles (LDMVs) also change marrow cell phenotype by inducing them to express pulmonary epithelial cell-specific mRNA and protein. These changes are accentuated when microvesicles isolated from injured lung....

The hierarchical models of stem cell biology have been based on work first demonstrating pluripotental spleen-colony-forming units, then showing progenitors with many differentiation fates assayed in in vitro culture; there followed the definition and separation of "stem cells" using monoclonal antibodies to surface epitopes and fluorescent-activat...

4794 We propose that the long-term multipotent marrow renewal stem cell is on a continuum of change in potential tied to cell cycle stage. Furthermore our data indicate that marrow stem cells cannot be defined on a clonal basis and that purification of stem cells, as is currently carried out, leads to a biased population which provides only limited...

4803 We have previously shown that murine bone marrow cells co-cultured opposite murine lung cells, but separated from them by a cell-impermeable membrane, express pulmonary epithelial cell-specific mRNAs, including Surfactants A-D, Aquaporin-5 and Clara Cell Specific Protein. This effect appears to be enhanced when the lungs used in co-culture are...

4799 We have previously shown that microvesicles derived from irradiated murine lung cells enter murine bone marrow cells and induce expression of the pulmonary epithelial cell-specific mRNAs Surfactants A-D (Sp-A-D), Aquaporin-5 (Aq-5) and Clara Cell Specific Protein (CCSP). The early mRNA increases are due to direct delivery of mRNA and due to th...

4223 Acquired amegakaryocytic thrombocytopenia is a rare disorder in which there is a marked decrease in bone marrow megakaryocytes leading to severe thrombocytopenia with preserved hematopoeisis in the remaining lineages. The clinical course is variable and no standardized treatment exists. Multiple cases in the literature report treatment using i...

Type 1 Von Willebrand Disease (VWD) is the most common congenital bleeding disorder, affecting 1% of the population, and caused by a quantitative deficiency of Von Willebrand Factor (VWF). In addition to mucosal bleeding, VWD patients often suffer postoperative bleeding, leading to significant morbidity. Thus, a preoperative diagnosis could potenti...

High levels of alpha(v) integrin expression by fetal muscle suggested that vector re-targeting to integrins could enhance adenoviral vector-mediated transduction, thereby increasing safety and efficacy of muscle gene transfer in utero. High-capacity adenoviral (HC-Ad) vectors modified by an Arg-Gly-Asp (RGD) peptide motif in the HI loop of the aden...

Adenoviral (Ad) infection involves attachment mediated by the Ad fiber protein binding to the coxsackievirus-adenovirus receptor (CAR) of a target cell and internalization facilitated by the interaction of the Ad penton base protein with alpha(v) integrins. To understand the relative importance of the Ad binding and internalization steps for the tr...

A muscle biopsy from an X-linked muscular dystrophy pedigree showed normal dystrophin and dystrophin-associated proteins. Linkage to multiple markers within the dystrophin gene (LOD=2.7, theta=0) indicated a primary dystrophinopathy. Sequencing of the entire dystrophin RNA revealed a single missense mutation (D3335H) in the unique carboxyl-terminal...