Directory of Faculty & Research Interests
Stem cell research in my lab focuses on the potential of these cells for repair of central nervous system injury,
the mechanisms of repair, and the basic biology of how stem cells respond to the injured CNS environment to incorporate
into a niche. Human CNS stem cells propagated as neurospheres (CNS-SCns) have the ability to differentiate into neurons,
oligodendrocytes and astroctyes in vitro and migrate extensively following transplantation into uninjured parenchyma.
Together with Dr. Brian Cummings, we have shown that these cells also survive and engraft in contusion-injured
immunodeficient NOD-scid mice, adopt site-appropriate cell morphologies, preferentially differentiate into neurons
and oligodendrocytes, and promote recovery of locomotor function. Functional recovery is dependent on hCNS-SCns survival,
and electron microscopy demonstrates both myelination of host axons (color photo) and formation of human-mouse synapses
(black and white photo). Our current research seeks to experimentally test the basis for observed functional recovery,
evaluating the roles of functional engraftment versus modification of the host response to injury, and investigating the
effect of the immune environment and prospective generation of cells with multipotent potential on engraftment, cell fate,
integration with the host, and recovery of function.
The research program in the Busciglio lab is directed to characterize the molecular and cellular
mechanisms of neuronal dysfunction and death in the brain of Down's syndrome and Alzheimer's disease patients. Utilizing
primary neuronal cultures derived from normal and DS brain specimens, we have identified chronic mitochondrial alterations in
DS cells derived from CNS as well as from peripheral tissues. The focus of our investigation is the influence of specific
genes localized in chromosome 21, and therefore over expressed in DS, on the alterations observed in DS mitochondria, and
consequently on several clinical phenotypes associated with DS, including mental retardation and Alzheimer's disease, both
of which are associated with energy deficits. The emergence of new technologies to maintain and characterize stem cells as
well as neuronal precursor cells give rise to new possibilities in terms of experimental paradigms for the study of
neurodegeneration in human neurons, and for the development of stem cell-based therapies to treat aged-related neurological
conditions. We utilize neuronal precursor cells derived from normal and DS brain tissue to characterize the role of mitochondrial
dysfunction in DS and AD. Another important aspect of our research is to understand the role of mitochondria in stem cell survival,
proliferation and differentiation. We believe that this information is critical to expand our ability to manipulate stem cells,
with the ultimate goal of designing efficient stem cell-based therapies.
Our laboratory works in two areas of stem cell research. One area concerns the role of retinoid and FGF signaling in the
differentiation and regeneration of auditory hair cells. Both pathways are involved in the differentiation of hair cells
and retinoic acid can induce regeneration of hair cells under certain circumstances. Understanding the mechanism through
which this regulation occurs would facilitate the control of this process and could provide an important new therapy for
hearing loss. The second area concerns breast cancer stem cells, which may be reservoirs of tumor-causing potential.
We previously showed that treatment of breast cancer cells with compounds that activate the steroid and xenobiotic receptor,
SXR leads to growth arrest and apoptosis. Understanding the role of SXR in the proliferation and differentiation of breast
cancer stem cells could be important for targeting therapies to these cells, in vivo.
One of the defining characteristics of stem cells, at least in model systems, is that they undergo a specialized type of
mitotic division called asymmetric cell division (ACD), producing one division product that remains as a stem
cell (self-renewal) and one that enters a differentiation pathway. The genetic control of ACD has been thoroughly
analyzed by genetic methods in the fruit fly Drosophila, and Dr. Bryant's laboratory has contributed to this work by
identifying and characterizing one of the critical components, the protein Pins (Partner of Inscuteable). They have
shown that this protein is localized asymmetrically during ACD, so that it is delivered to the division product that
remains as a stem cell rather than the specialized cell. They have also shown that this protein is required for ACD and
that, in its absence, the stem cell population favors the self-renewal pathway and generates brain tumors. They have
identified two human counterparts of the Pins protein and shown, in collaboration with Dr. Phillip Schwartz at the
Childrens' Hospital of Orange County, that one of them, called LGN, is localized asymmetrically in human neural stem cells
(green in the figure, with DNA in blue and beta-tubulin in red), providing one of the first pieces of evidence that these
cells undergo ACD. They are now investigating the localization and function of more human homologs of the Drosophila proteins
controlling ACD, and extending the work to other types of human stem cells. The work will help us to understand how stem
cell development is controlled, so that these cells can be used safely to help replace lost or damaged tissues and organs.
This photomicrograph of the olfactory epithelium is stained with fluorescent markers
that show proliferating stem cells (green) in the basal compartment of the epithelium (red). As these stem cells
differentiate into neurons, they will migrate upwards and extend axons into the brain. Since the olfactory epithelium
is unique in its ability to regenerate neurons following injury, studying this tissue is yielding clues about the molecules
that are permissive and restrictive to regeneration in the mammalian brain.
Diabetes occurs when the pancreas contains defective cells that do not produce sufficient quantities of insulin. b-cells
normally produce insulin and help the body move the glucose into cells. Our mission is to develop stem cell
approaches that will facilitate the production of b-cells for the treatment of type I diabetes. We use both mouse
embryonic stem cells and frog embryos to follow the development of the animal to the time when it makes a pancreas.
We have identified over 50 genes specifically expressed or enriched in the pancreas, and hope to validate the results in vivo.
Using these genes as pancreas markers, our plan is to learn to steer the differentiation of ES cells into pancreatic lineage.
Our research addresses mechanisms of brain development and plasticity, with a focus is on circuitry in the auditory system. We are looking at how the actions of several axon guidance molecules are coordinated to bring about precise functional circuits.  We have found that the Eph family proteins, a large family of axon guidance molecules, are necessary for the formation of frequency maps in auditory circuitry. In addition, these proteins are important for guiding axons at the midline of the brain. These functions are critical for the formation of auditory brainstem circuitry. The auditory system can adapt to changes in auditory input. After early removal of cochlear input, neurons modify their circuitry in very precise ways so that the brainstem nuclei retain high levels of innervation. We have recently shown that extensive reorganization can occur later than was previously thought, suggesting that the auditory nervous system can adapt to changes in mature animals. The extent of deafferentation-induced plasticity can be modified by age, type of lesion, and mutations in Eph proteins. We are using this model to measure the effectiveness of potential molecular and cellular therapies to enhance brain recovery.
My lab is focused on CNS repair in humans. This involves understanding pathology, innate repair processes, and issues
related to therapeutic intervention. The main tools we use to approach these issues are detailed behavioral/neurological
examination, anatomical brain imaging, functional MRI, perfusion MRI, and transcranial magnetic stimulation (TMS). The
principal populations in which we are focused are those with stroke or with spinal cord injury. The cell therapy that is
our current focus is autologous mesenchymal stromal cells.
Skin epidermis is derived from the pluripotent ectoderm, which also gives rise to neuroectoderm, precursor of the nervous
system. In an ectodermal cell's path to become epidermis, it faces at least three critical decisions: 1) not to become a
neural cell, 2) not to become an appendage (hair follicle or mammary gland) cell; 3) to cease proliferation and differentiate
into a terminal cell that carries an essential protective function for organism's survival. What genes or genetic pathways
govern or modulate these choices? What happens if these genes/pathways go awry? The long-term goal of my research is to
use a multidisciplinary approach involving transgenic mice, in vitro cell and organ culture, and molecular biology to address
these questions. Currently, we focus on the role of canonical Wnt signaling, one of the most important signaling pathways
involved in both normal and malignant development, and its putative target genes, particularly the Ovo zinc finger
transcription factors, in controlling epidermal development and differentiation.
One of the major components of aging is the progressive decrease in the regenerative ability of the skeletal
system and hence reduces its ability to heal naturally. Although many factors contribute to this decline, one
key component is the age-related changes in differentiation markers in osteoblast and chondrocyte biology. Our
work is focused on the repair and regeneration of bony and cartilage defects. The studies are designed to
evaluate the differentiation potential of human processed lipoaspirate derived adult stem cells (ASCs) into
osteoprogenitor and pre-chondrocytes cells which in turn are capable of differentiating into mature osteoblast
and chondrocytes, respectively both in vitro and in vivo.
Besides studying the translational impact of these cells, we are also studying the biology and physiological
behavior of differentiation of these cells. One more component of the study is to ascertain the behavioral
biology of these differentiated cells on various scaffolding materials (polymers), the backbone of bony
reconstructions. A protocol has already been developed for in vitro long term differentiation of ASCs into
osteoblasts and chondrocytes progenitor cells.
Throughout mammalian development, cells gradually decrease in potency as they assume the specialized characteristics
of differentiated tissues. Germ cells, charged with transferring the genome between generations, are unique in their
ability to re-create a totipotent cell. Pluripotent stem cells harbor an ability to differentiate along endodermal, mesodermal
or ectodermal cell lineages. Our laboratory is interested in two critical aspects of germ cell and stem cell development.
One aspect is the regulation of developmental potency within the mammalian germline and within pluripotent stem cells derived
from germ cells (embryonic germ cells, or EG cells) and from early embryos (embryonic stem cells, or ES cells). Learning how to
control stem cell potency may point to new methods of maintaining EG or ES cells in an undifferentiated state for a prolonged
period of time, or avoid the tumorigenic potential of these cells when transplanted into animals. The second focus of our work
is meiosis, the reductive cell division exhibited by germ cells during gamete formation. Meiotic deficiencies can produce
defective gametes which, in turn, are associated with birth defects or fetal loss. Investigators in the Donovan Lab utilize
the many techniques available to modern cell biologists, including transgenic and knockout mice, confocal microscopy, microarray
analysis, chromosome mapping, RNAi and advanced cell culture techniques required of EG and ES cells.
Cells of various types including adult stem cells derived from bone marrow have proven beneficial when
embedded in scaffold materials for bone reconstruction. However, problems arise when trying to embed stem
cells throughout large-scale (greater than 1mm in thickness) three-dimensional scaffolds. To over come this problem,
we have developed Solid Freeform Fabrication (SFF) techniques to engineer large-scale engineered bone constructs.
In this research, each thin layer is seeded with osteoprecursor stem cells individually and then stacked to form the
3-D structure. Following implantation, these cells survive by the simple diffusion of nutrients into the scaffold,
and proceed to mature into osteoblasts and osteocytes that synthesize calcified bone matrix to reconstitute the bone
defect. The research involves the use of dynamic finite elements models combined with automated percussion probe
measurements (Figure 1). The goals of the work are to (1) develop a better understanding of the mechanical behavior
of these scaffold materials under physiologically relevant loading conditions and (2) how this behavior might be
optimized for the differentiation and proliferation of embedded stem cells.
My laboratory's work is focused on the repair and regeneration of critical nerve defects in peripheral nervous
system (PNS) and spinal cord injuries (SCI). The approach is to evaluate the differentiation potential of human
processed lipoaspirate derived adult stem cells (ASCs) into neural progenitor cells which in turn are capable of
differentiating into mature neurons and/or glial cells both in vitro and in rat model. Besides studying the
translational impact of these cells, we are also studying the biology of differentiation of these cells. The study
on the use of ASCs in SCI is done in collaboration with Hans Keirstead.
We have already developed an in vitro differentiation model of ASCs into early neural progenitor cells which can
retain the differentiation status of these cells over a long period of time overcoming the potential of these cells
to dedifferentiate at early stages of differentiation.
The focus of our stem cell research is on how to induce massive proliferation, migration and differentiation (PMD)
of adult stem cell progenitors in the injured adult nervous system system. We are presently studying PMD and behavioral
recovery in a long term stroke model in rodents following middle cerebral artery occlusion and in Parkinson's disease models.
In late 2005 we will also begin studies on the mobilization of stem cells and bioadhesives for novel peripheral and central
neural interfaces for prosthetic devices. We are also involved with the Brain Imaging Center in molecular imaging (PET) and
fMRI studies to label and monitor regeneration in animal and human models of Parkinson's disease, schizophrenia, and
Alzheimer's disease.
We are interested in the mechanisms that control the generation of functional neurons from stem cells.
Using mouse and human neural stem cells, we have begun to identify genetic and environmental cues that
regulate the proliferation (green nestin-positive cells in picture) and neuronal differentiation
(red TuJ1-positive neuron in picture) of these cells. We are also exploring three-dimensional biomaterials
that would be suitable as transplantation scaffolds for both neural and human embryonic stem cells. In a
collaboration with Drs. Noo Li Jeon (Biomedical Engineering), Abe Lee (Biomedical Engineering), and Edwin
Monuki (Pathology), we are using engineered microfluidic platforms to prospectively sort stem cells and
expose them to continuous gradients of soluble factors in order to determine optimal conditions to
specify differentiation.
Dr. Sidney Golub combines his experience as a biomedical research scientist (he specialized in cancer immunology)
with his four year experience in the nation's capital working on science policy issues. Stem cells are an important
challenge for the development of science policy in this country, and Dr. Golub has focused on understanding the variations
of policy among the states, between the states and the federal government, and between the USA and other technologically
advanced countries. He has made an effort to keep the UCI Stem Cell Center leadereship up to date on the political and
policy aspects of stem cell science.
One research effort in Guan group aims to develop new biomaterials as scaffolds for tissue regeneration.
Recently we have made a few key breakthroughs in designing new biomaterials using saccharide and peptide
building blocks. The first class of novel biomaterial is a saccharide-derived side-chain polyether and
the second class is a family of saccharide-peptide hybrid copolymers. These new biomaterials are fully
biodegradable, have no cytotoxicity and immunogenicity, and exhibit high structural flexibility. These
unique attributes make them ideal candidates for interactive biomaterials applications, including those
in controlling stem cell differentiation and tissue engineering. Capitalizing on the versatility of these
new materials, we collaborate with biomedical researchers to investigate basic structure-property
relationship of our new biomaterials for use as scaffold templates suitable for tissue engineering
applications. The goal is to design new biomaterials as synthetic extracellular matrix (ECM) analogs to
control and regulate stem cell differentiation.
In rodents, neural progenitor cells delivered to the vitreous can integrate into the ganglion cell layer of the
retina, turn on neurofilament genes, and extend neuritis into the host optic nerve. The lab is now developing a
knockout mouse model for a stem cell-based treatment. We believe we have several advantages in treating patients
with optic atrophy using stem cells. First, the eyes are a very accessible organ for delivering stem cellsa factor
that simplifies the stem cell therapy. Second, many degenerative retinal diseases share the pathogenesis of apoptosis
of retinal ganglion cells. We may apply what we discover in optic atrophy to other retinal degernative disease. Curretly,
we are creating knockout model and to use the animal model to perform stem cell therapy. This project is a collaborative project
with Dr. Doug Wallace, Director of the Center for Mitochondrial Medicine and Genetics. Dr. Wallace discovered the genetic
cause of Leber's disease, which shares many clinical features and pathological changes with optic atrophy. We will also
collaborate with many clinicians Dr. Arnold Starr, neurologist, Dr. Bose, ophthalmologist, and Henry Klasson,
ophthalmologist and stem cell biologist. By collaborating with several different clinicians and
laboratories we will be able to take a multidisciplinary approach towards developing stem cell
therapy for patients with optic atrophy.
The primary interest of our lab is to study the molecular basis of genetic syndromes and to
develop stem cell (ES) therapy. Currently, our lab is focusing on the following areas.
TBX3 and Human Embryo Stem Cell. To study the role of TBX3 in breast cancer and
embryo stem cell differentiation. TBX3 is also a T-box transcription factor. Mutation
of TBX3 causes Ulnar-Mammary syndrome characterized by hypoplasia and absence of the mammary
gland. Oveexpression of TBX3 plays an important role in breast cancer. To study the role of TBX3
in breast cancer, we are working on an animal model, and analyzed TBX3 expression in human breast cancer
tissue. By working with animal and breast cancer tissue, our research aims to optimize the clinical relevance
of our work. Recently, we and others have fond that TBX3 is regulated by BMP4 in human ES cell. To identify the
downstream targets of TBX3, we performed the promoter array to examine the genome-wide binding site for TBX3 to further
elucidate TBX3 function in ES cells defferntiation.
The Genetic basis of optic atrophy and stem cell therapy. Our lab is interested in stem cell therapy in retinal degenerative
diseases, particularly in optic atrophy. Optic atrophy is one of the most common genetic causes of blindness. In human, mutations
of OPA1 cause autosomal dominant optic atrophy (A). OPA1 is a nuclear gene whose product is localized in mitochondria.
Mutation of Opa1 in mouse ES cells causes fragmentation of Mitochondrion (C) comparing with wild-type cells (B)
We use mouse and human neural stem cells to understand how the cerebral cortex develops and how cortical
birth defects arise. Morphogen gradients are fundamental to animal development, and morphogen defects are primary
causes of human malformations involving the cerebral cortex. Nonetheless, tremendous controversy remains about the
mechanisms by which morphogen gradients act on the developing brain. Much of the controversy revolves around the
inability to distinguish morphogen actions. To date, studies on this issue have relied on traditional cell cultures,
which have inherent inefficiencies and biological limitations as models of natural gradients. We have developed a
high-throughput microfluidic platform that can closely mimic the shape of morphogen gradients seen in living organism.
Because stable and continuous gradients can be applied to the cells, it provides significant advantages over traditional
cultures for investigating the effect of different gradients. The microfluidic platform not only advances our understanding
of cortical development and malformations but should also provide a versatile tool with a number of potential basic and
clinical applications.
Dr. Keirstead's current stem cell research utilizes federally-approved and non-federally-approved hESC lines.
He developed a method to differentiate hESC lines into high purity oligodendrocyte progenitor populations,
demonstrating for the first time that hESC lines can be differentiated into high purity CNS populations,
and making available for the first time high purity human oligodendroglial lineage cells for research and therapy.
He is currently investigating points of control in the maturation of stem cells to various CNS lineages besides
oligodendrocytes.
He has also recently demonstrated the regenerative ability of these cells in animal models of spinal cord injury
and multiple sclerosis, where they remyelinate and facilitate functional locomotor recovery. He transplanted these
cells into acute and chronic spinal cord injured adult rats, and rodent models of multiple sclerosis, to investigate
their ability to survived, differentiate into myelinating oligodendrocytes, and restore locomotor ability. In this
manner he is comparing the regenerative efficacy of different hESC lines, as well as young and old passage hESC lines.
He is also investigating the ability of transplanted hESC derivatives to migrate in the adult CNS following manipulation
of the environment, including exercise of animals. Finally, he is conducting gene chip and other molecular analyses of
hESCs and their derivatives to determine points of control during their differentiation, and the effects on hESC
derivatives following exposure to the injured CNS.
Lee studies neural stem cells from mice and humans using microfluidic devices to help researchers understand the
factors dictating stem cell differentiation to develop micro-devices. His research primarily focuses on the
development of integrated micro and nano fluidic chip processors for the manipulation of biomolecules, cells and
the reagents for on-chip bioassays and synthesis of biomaterials. He has developed a microfluidic platform that
can sort biological cells based on its electrical characteristics and correlate the different groups with the
differentiation inclination of the cells. These integrated chip processors can also be used for sample preparation
of biological fluids to streamline the overall cell analysis process. Other applications that Prof. Lee is pursuing
for these fluidic processors include programmable precision production of biological reagents for bioassays and
drug delivery, high sensitivity biosensors, on-chip high throughput screening, and automated chips for point-of-care
diagnostics.
Dr. Meyer's research interests include feature segmentation in digital images from histological sections,
cryosections, confocal laser-scan microscopes and other modalities (CT, MRI, etc.) In his laboratory, he and
his team recently developed methods for identification and tracking of axon remyelination after stem cell treatment
in rat spinal cord injury sites.
Dr. Meyer has an expertise in large-scale scientific visualization, biomedical imaging, digital image processing, interactive
rendering and virtual reality.
His research efforts are aimed at developing interactive image processing and rendering methods for large scientific data sets.
He has developed multiple level-of-detail data representation techniques based on hierarchical space-subdivision algorithms and
wavelet-based compression schemes, enabling interactive, frequency-based feature detection, data storage, transmission and
rendering of large-scale cross-sectional and volumetric data sets.
We use neural stem cells from mice and humans to help us understand how the cerebral cortex develops and
how cortical birth defects arise. Stem cell cultures are complemented by mouse genetics and explant culture systems,
which are used for gain- and loss-of-function studies on the signals and genes that regulate cortical stem cells.
Together with Lisa Flanagan (Pathology), Abraham Lee and Noo Li Jeon (Biomedical Engineering), we are also using
microfluidics to model morphogen gradients in brain development and to develop novel tools for culturing and
sorting stem cells with an eye toward therapeutic application.
Our work has elucidated the biochemical pathways involved in the formation and deactivation of two endogenous
cannabinoid lipids, anandamide and 2-arachidonoylglycerol (2-AG), and uncovered several physiological functions
served by these molecules. We have also developed various classes of pharmacological agents that target endocannabinoid
deactivation, producing analgesic, anxiolytic and antidepressant effects. In addition, we have discovered the molecular
mechanism of action of a novel class of lipid messengers, the fatty-acid ethanolamides (FAE), natural ligands of the
nuclear receptor PPAR-alpha that are involved in the control of feeding, pain and inflammation.
Predictably controlling the commitment of embryonic and adult stem cells is critical to widen their use
in regenerative medicine applications. In the case of adult bone marrow-derived mesenchymal stem cells (MSCs),
the roles of various soluble factors in promoting osteogenic differentiation have been extensively studied.
Much less is known about the instructional role of the extracellular matrix (ECM) to regulate the phenotypic
transition between growth and differentiation. Dr. Putnam's laboratory is focused on addressing this question,
driven by the hypothesis that ECM chemistry and mechanics coordinately influence stem cell commitment. Knowledge
obtained from basic cell biological studies is used to guide our design of biomaterials that act as synthetic ECM
analogs. Such materials can potentially be used as vehicles to deliver cells in vivo and to confine them to a specific
anatomic location. We are also exploring the ability of such materials to act as in vitro stem cell niches, permitting
the maintenance of "stemness" without the use of animal-derived feeder cell layers.
The O'Dowd and Smith labs, in collaboration with the Schwartz lab, are investigating the functional
properties of postmortem human neural progenitor cells (SC27) co-cultured with primary neurons from other species.
In previous studies we have shown that SC27 cells, harvested from postmortem human cortex, can be induced to
differentiate into cells with morphological and biochemical properties characteristic of neurons. However,
while some of these cells were capable of firing regenerative responses characteristic of immature neurons, none
of the cells were able to generate mature overshooting action potentials. The goal of our present studies is to
determine if contact with primary neurons from other species (mouse, chick) can stimulate differentiation of SC27
cells into cells with functional characteristics of mature neurons including the ability to fire repetitive
overshooting action potentials and synaptic connections. As shown in Figure 1, our preliminary studies show we
can identify GFP+ SC27 differentiating in cultures of cortical neurons from early postnatal mouse. We will compare
the electrophysiological properties of these cells with SC27 cells grown on human fibroblasts.
Sander, Maike, M.D. Department of Developmental & Cell Biology Embryonic mouse pancreas with progenitor cells and hormone-producing cells marked in different colors
Dr. Sander's laboratory uses genetically engineered mice to identify transcription factors that control the formation of insulin-producing ß-cells in the pancreas. To efficiently reproduce ß-cell development from stem cells in vitro, the lab has developed mice that can be used to monitor ß-cell development in vitro as well as to isolate and characterize different populations of ß-cell precursors. The knowledge gained from these experiments will be applied to the in vitro differentiation of ß-cells from mouse and human ES cells. For example, we will be able to determine whether critical transcription factors play similar roles in human ß-cell differentiation and whether these factors can be used to direct human ES cells toward the pancreas lineage.
The focus of our research has been centered for many years on the mechanisms controlling the generation of totipotent stem cells occurs through gametogenesis, a complex, sex-specific differentiation program (for an overview of our interests see Nature (2005) 434: 583-589). Germ cells have the unique capacity to start a new life upon fertilization. The mechanisms of gene regulation in germ cells are highly specialized, and we have identified a number of unique molecular devices that gem cells utilize to elicit a fine control of pre- and post-meiotic transcription. In addition, unique epigenetic modifications exist in germ cells, including a remarkable set of germ cell-specific histone variants and a highly specialized use of DNA-methylation. Their function in chromatin remodeling, meiosis and gene expression is crucial. In the male, the haploid germ cells undergo the spectacular histone-to-protamine transition process which reshapes the nucleus and prepares it for fertilization. The epigenetic control of these processes has a number of outstanding features and its comprehension is likely to have far-reaching implications for human health and reproduction.
The unraveling of the regulatory pathways and molecular mechanisms that govern the differentiation program of germ cells is likely to provide essential hints to the biology of stem cells of non-germinal origin. In particular, our studies have identified highly specialized pathways for the control of RNA processing which determine the timing of the differentiation steps leading to germ cells maturation.
This research aims at testing the hypothesis that hydra stem cell growth and differentiation are mechanosensitive.
The studies on the influence of externally applied stresses on the regenerative ability of hydra stem cells will shed
light on the mechanical aspects of stem cell behaviors, and may ultimately lead to developing a tool to facilitate the
control of stem cell growth and differentiation for regenerative medical applications.
Hydras are remarkable for their powers of regeneration. When a hydra is cut into fairly large pieces, each piece develops
into a complete individual. Small pieces of hydra, when placed in contact with each other, grow together to form a complete
individual. The simplicity and robustness of the regenerative ability in hydra provide a naturally elegant experimental tool
to study stem cell differentiation. Hydra regeneration is easily observable under an optical microscope. The differentiation
into either head or foot regions represents a simple "binary" system. Furthermore, its small size affords relatively simple
experimental setups. In this research work, we pressurized hydra pieces under water over a period of one week, and observe
and quantify the regenerative abilities periodically. To apply static mechanical pressure, a 6-foot water column filled
with sterilized water was used. Several dissected hydra specimens were introduced into chambers fabricated from
poly-dimethyl-siloxane (PDMS) and lowered in to different depths inside the water column. The specimens
were examined at regular intervals over the course of 168 hours. At these depths, the dissected hydra experienced
different amount of pressures. A second means to apply mechanical pressure were conducted inside a pressure vessel, in
which hydra specimens were placed in open PDMS wells. The pressure vessel was pressurized to various levels, ranging from
0 to 10 psi, and monitored every 24 hours for 168-hour long trials. Data in terms of amount of bud growth and tentacle
regeneration were collected with respect to degree of mechanical force applied. Based on our findings so far, there
appears to be a statistically significant correlation between the levels of mechanical compression, available resources
(including number of stem cells), and the ability for hydra to regenerate. Additional work is underway to control the
amount of dissolved oxygen in the media to eliminate this as a confounding factor. The long range goal is to include other
stem cell types in the study.
Dr. Wang's laboratory is investigating how growth factors and heat shock proteins modulate development of
stem cells and cardiac muscle cells. His laboratory has identified potential mechanisms through which heat
shock proteins modulate intracellular signaling network and enhance cell development and survival.
Dr. Wang is directing the Joslin Diabetes Center at UCI, which has engaged a coordinated program to translate
basic stem cell research into islet cell replacement therapy for patients of Type 1 diabetes. Scientists
associated with this center is developing novel strategies to generate unlimited supply of islet cells, to
prevent autoimmune destruction of lslet cells, to transplant islet cells, and to forcast the impact of stem
cell therapy on health policy.
Deregulation of genes important for proper cellular differentiation is a major cause of developmental
abnormality in humans. Histone modifications and chromatin structure organization play critical roles
in regulating gene expression during the cell cycle and differentiation. Our laboratory is interested
in characterizing chromatin structural organization in human cells. We focus on multiprotein complexes
termed "condensin" and "cohesin", which are essential for higher order chromatin structure formation, chromatin condensation
and sister chromatid cohesion. Although originally found to be critical for mitotic chromosome organization and segregation,
accumulating evidence suggests that these complexes are also important for developmental gene expression through higher order
chromatin structural modulation. We utilize biochemical, cytological and molecular methods, including chromatin crosslinking
and immunoprecipitation (ChIP), chromatin conformation capture (3C method), immunofluorescent staining, and RNA interference,
to address the role of chromatin structure in developmental gene regulation in ES cells, adult stem cells and cells at different
differentiation stages. In collaboration with Dr. Peter Donovan's laboratory at UCI, we are analyzing chromatin organization
in human ES cells and studying how this organization is altered during cellular differentiation and in human diseases.
The Zhou laboratory is interested in investigating the molecules that control the migration of neural stem cells
or neural progenitors. Recently, we have demonstrated that PK2, a secretory protein, is essential for the normal
migration of olfactory bulb neural progenitors (Science, 308, 1923-1927, 2005). Approaches of in vitro explant
culture and transgenic mice are being utilized.