Summary National Heart, Lung, and
Blood Institute Working Group on Tissuegenesis and Organogenesis for
Heart, Lung, and Blood Applications
National Institutes of Health Two
Rockledge Centre Bethesda, MD August 13, 1999
TABLE OF CONTENTS
Background
Introduction
Basic Science and
Technology
Clinical Problems
Summary of Recommendations
Agenda
Roster
BACKGROUND
On August 13, 1999, an NHLBI Working Group Meeting on
Tissuegenesis and Organogenesis for Heart, Lung, and Blood Applications was
held at the National Institutes of Health, Rockledge Two Building. The one-day
meeting, sponsored by the NHLBI Tissuegenesis/Organogenesis Interest Group
(TOG), consisted of a series of discussions on five major topics as they
related to advancing research toward the goal of growing tissues and organs for
the repair or replacement of those lost or damaged due to injury or disease.
The topics included: 1) Developmental Biology of Stem Cells, Tissues and
Organs; 2) Gene Regulation in Tissues and Organs; 3) Structural and Functional
Histoarchitecture; 4) Vascularization of Growing Tissues and Organs and; 5)
Response to Injury. The Working Group Participants (see attached roster)
addressed the state of the science and provided recommendations on ways to
provide broader opportunities for research and development in this field to
prepare for the future.
INTRODUCTION
Tissuegenesis and organogenesis are defined here as
the formation of new tissues or organs to replace damaged or absent function.
In one paradigm, progenitor cells or stem cells that will produce the major
tissue-specific cell type (e.g., cardiac myocytes, lung epithelium) are seeded
directly into the damaged site, or a temporary scaffold is placed in the site,
to initiate a regeneration process, and supporting connective tissues (blood
vessels, lymph, nerve, immune) are induced to grow in from surrounding tissue.
For example, it is desirable to repair the infarct-induced damage to cardiac
tissue rather than replace the entire heart by transplant. This might be
achieved by implantation of fetal or neonatal cardiomyocytes or stem cells into
the damaged tissue to restore contractility. In a second paradigm, tissue is
grown in vitro for subsequent transplantation. This paradigm is used clinically
in the hematopoietic system and is under development for others. In the case of
cardiac repair, for example, a "patch" of tissue or tissue precursor might be
grown in vitro and then grafted onto diseased tissue.
Heart, lung, blood, and vascular
tissuegenesis/organogenesis share some common scientific challenges, and can
all benefit from some common technological approaches. These include
identifying appropriate sources of stem cells, leaning how to accomplish cell
expansion and differentiation, and understanding the principles necessary for
formation of complex multi-cellular structures, including vascular networks. At
the same time, each application area also presents its own challenges that
relate to specific clinical problems and the unique biology and physiology of
the tissue. Research should thus proceed along two parallel fronts,
cross-cutting basic science and technology, and focused approaches aimed at
well-defined clinical problems.
BASIC
SCIENCE AND TECHNOLOGY
Common themes include: (1) understanding how tissues
develop during embryogenesis and how damaged tissue successfully heals itself
(i.e. in the absence of fibrosis), and; (2) identifying both cellular elements
(e.g., circulating or resident progenitor cells) and environmental elements
(matrix, cytokines, growth factors) that are required for tissue healing. These
will permit regeneration to be achieved reproducibly and cost-effectively in a
clinical setting. Several specific topics are included in these two themes.
Progenitor Cell Biology
In one model of tissuegenesis, differentiated tissue
would be generated from progenitor or stem cells either ex vivo, by recruitment
to the site of interest, or used in vitro in combination with a scaffold to
create new tissue. One critical area of fundamental investigation is in
progenitor cell formation and differentiation. (In some cases this may rely
upon stem cells/progenitor cells with capacity for self renewal). This
requires: 1) development of cellular markers to distinguish such cells; 2)
identification in the adult of where such cells reside; 3) understanding of
factors and matrix needed to support their growth and morphogenesis and; 4)
evaluation of methods to "erase" differentiation and thereby generate cells
capable of becoming progenitor cells of other tissue. Regardless of whether
stem cells, rather than more differentiated tissue-derived populations, are
ultimately used in an application, the long-term function and maintenance of
the tissue requires appropriate tissue kinetics and turnover. Thus progenitor
cell biology is a foundation for tissuegenesis and organogenesis.
A key bottleneck in the development of stem
cell-based therapies is the relative paucity of markers for stem cells and
lineage progression, particularly for systems other than the hematopoietic
system. Development of markers is hindered by the time-consuming nature of
assays for differentiation, or the frank absence of reliable assays in some
tissue systems. Methods for rapid identification of putative markers on
candidate cell populations are also relatively poorly developed. Resources
directed to both these areas would greatly enhance research in tissuegenesis of
all systems, including those of interest to the NHLBI.
Relatively few tissues have been characterized as
having highly accessible progenitor cells; the presence of highly plastic and
accessible stem cells from other compartments, especially the circulation or
bone marrow, would expand the possible applications. Harvesting stem cells from
lung, for example, may be excruciatingly complex, while harvest from peripheral
blood is relatively straightforward. Emerging data suggest there are stem cells
which are highly plastic, and this fact has enormous implications for
tissuegenesis.
Little is known about the environmental effects
leading to stem cell self-renewal, replication and differentiation. To address
this, better assays are needed to follow the fate of transplanted stem cells in
vivo; such studies could go hand in hand with research in stem cell-based gene
therapy. It will likely be desirable to expand stem cell populations in vitro.
To accomplish this, rapid/high-throughput in vitro assays are needed to
systematically investigate effects of environment (e.g., growth factors and
cytokines) on cell differentiation, proliferation, and mobilization.
Obtaining stem cells by isolation from natural
sources in the body may ultimately prove to be unfeasible, or too cumbersome
for routine clinical use. One alternative approach to generate cells capable of
appropriate differentiation may be to "erase" the differentiation of somatic
cells through approaches such as altering DNA methylation. This could
potentially increase the availability of cells and allow patient-specific
tissues to be generated on a wider basis. A second approach is use of embryonic
stem cells; this approach requires methods for reproducible, controlled
differentiation of these cells, a goal far from being met.
Angiogenesis
With few exceptions, tissues in the heart, lung, and
blood system contain dense capillary networks which are richly perfused. For
metabolically active tissues like heart and marrow, parenchymal cells are
generally within a few tens of microns from a capillary. This limits oxygen
diffusion in such highly cellular and active tissue to about 150 microns.
Tissue vascularization is thus a key, and a limiting, process for tissuegenesis
and organogenesis.
For cells implanted directly into a site,
angiogenesis would have to be derived from surrounding tissues. Despite the
identification of many regulating molecules, and despite examples of
angiogenesis in response to a single growth factor, many key issues regarding
mechanisms of angiogenesis remain. In experimental systems in vivo, it is not
clear that vessels induced by a single molecule are functionally equivalent to
normal vessels. This is not surprising, as normal physiological vessel growth
is regulated by multiple signals working in a concerted fashion. In addition,
the capillary beds of tissues are highly specialized to meet the needs of the
tissues, including such specializations as blood brain barrier and fenestrated
endothelium. Yet, the integrated signals which lead to the specific
architectures in tissues such as lung are not well-understood. In humans, the
results of growth factor/gene trials are mixed, and there is a strong need for
well-controlled clinical trials with functional endpoints. Little is known
about the temporal regulation of molecular players already identified and about
hierarchies of signaling during development of vascular networks in healing
tissues. Mechanisms of vessel regression are also relatively poorly understood.
In this regard, the role of endothelial cell-pericyte interactions in
regulating microvascular growth, function, and stability has not been well
characterized.
For tissues grown in vitro, moving beyond the
dimensions of a few hundred microns will require creation of a vascular network
capable of anastomosing with vessels at the site of implantation. This is a
complex problem requiring multiple advances in science and technology, as
tissues of any reasonable size must include vessels ranging from capillary beds
to arteries/veins and true perfused capillary beds have not yet been
demonstrated in vitro. Formation of larger vessels in vitro must also include
understanding of cell-interactions in formation and maintenance of tissue
structure, and the role of mechanical forces. Vessels grown in vitro must be
tested with appropriate functional assays, such as demonstration of
non-thrombogenicity.
Local Environment Analysis of
Matrix & Growth Factor Interactions
Lung tissue can regenerate after an acute injury in
some patients. Heart is not reported to generate new myocytes in the adult,
even after injury. Two major research areas important for
tissuegenesis/organogenesis arise out of these observations. First, what
environmental cues attract the cells that ultimately lead to repopulation? Are
there circulating stem cells which are drawn to sites of injury, and if so,
what are the signals that induce them to colonize a specific site? Second, what
are the factors that prevent regeneration of injured structures? Many
physiological factors represent the net outcome of positive and negative
factors acting together; understanding both types of signals is necessary to
achieve the desired balance.
Classically, these signals are thought of as matrix
(fixed molecules) and growth factors (diffusible molecules), with particular
molecules assigned to one category or the other. In regeneration processes,
matrix is being degraded and soluble fragments, as well as bound growth
factors, are being released. Further, with the accumulating data indicating
overlapping signaling pathways between adhesion receptors and growth factor
receptors, and with examples of membrane-bound juxtacrine systems such as
notch/delta, the lines of distinction between adhesion molecules, growth factor
ligands, and growth factor receptors are blurred.
Identification of molecules present is thus only one
component of understanding the process in a way it can be harnessed for
tissuegenesis. There is a need for engineering analysis and models of how
signals are presented physically and temporally, and how the cells integrate
these multiple overlapping signals to generate a response. Such quantitative
analysis and modeling is essential to provide a design basis for manipulation
of the environment to achieve tissuegenesis. For example, it has been observed
that epidermal growth factor (EGF) inhibits cell migration in some assays, and
stimulates cell migration in others. When the effects of EGF are considered in
the context of ECM adhesion and a biophysical analysis of cell migration, these
results are not contradictory. The process of cell migration depends in a
biphasic manner on the cell-substrate adhesion strength, exhibiting a maximum
at intermediate levels of matrix adhesion, and EGF serves to decrease cell
adhesion. Thus, when cells are plated on an intermediate density of matrix, EGF
may decrease cell adhesion to the point that cells can barely get a grip on the
substrate (migration inhibition). On the other hand, if the same cells are
plated on a high matrix density, the decrease in adhesion induced by EGF may
stimulate cell migration. Additional insights into the control of cell growth
and differentiation, and how to manipulate these processes for use in
tissuegenesis, might come from the field of cancer biology.
Local Environment Scaffold
Fabrication & Control of Cell Behavior
Generation of functional tissue or organ structure
requires a scaffold to guide the overall shape and three dimensional
organization of multiple cell types; i.e, a 3D physical set of cues. At one
extreme, this may be the existing tissue structure (e.g., in repopulation of
marrow with infused stem cells and in the proposed regeneration of heart muscle
by introduction of stem cells). The existing tissue structure may not provide a
conducive environment, though, if severely damaged and/or replaced by fibrous
tissues, and thus synthetic alternatives must be considered. The field of
biomaterials is only at the beginning stages of providing synthetic degradable
materials that can mimic key aspects of ECM; indeed, the design rules for what
is needed are only now being elucidated. Techniques for creating scaffolds with
complex architecture and chemistry e.g., to provide a template for a
branching vascular network are also relatively nascent and must be
developed significantly beyond current stages to address the needs of
vascularized tissues.
Although there remains much potential in the use of
growth factors and cytokines, alone or in conjunction with matrix, technical
and scientific barriers to clinical success are still significant.
Tissuegenesis overall requires the orchestrated unfolding of a series of
processes arranged in both temporal and spatial hierarchies, and each of the
individual processes, such as angiogenesis, is likewise governed by an array of
interlocking steps. Delivery of cytokines or other factors in a physiologically
relevant context remains a technical challenge; drug delivery techniques allow
sustained delivery, but not necessarily controlled on the time scale or length
scale necessary for tissue-genesis. It is also becoming more apparent that few
processes can be effectively stimulated by a single factor, and thus reliance
on exogenously added factors becomes even more technically challenging.
CLINICAL PROBLEMS
Clinical challenges in heart, lung, blood, and
vascular tissue engineering are wide ranging and at different stages of
development. Methods for regenerating the hematopoietic system are by far the
most well-developed, yet clinical demands for new therapies are still pushing
advances. The complexity of lung structure places it among the most challenging
of tissue and the one that has been pursued least by tissue engineering
approaches.
Heart
An estimated 4.6 million Americans suffer from
symptomatic heart failure. At end stage heart failure, transplantation is the
only therapy. However, transplantation is limited by donor availability to 2600
per year. Thus, many patients die awaiting a transplant. Common causes of heart
failure include coronary artery disease, cardiomyopathy, congenital
abnormalities, and hypertensive heart disease. In principle, cell engineering
and transplant procedures might be achieved to treat heart failure due to these
underlying diseases. For example, after a myocardial infarct, scar might be
replaced with muscle. This could be from cardiac cells (fetal, neonatal, or
engineered adult cells) or perhaps stem cells that are injected directly into
the scar area using either direct visualization or percutaneous technology.
Another interesting concept would be to grow a beating patch that could be
applied to the scarred tissue or sewn into the heart after removal of the
scarred tissue. Another possibility is total heart replacement with a tissue
engineered heart. However, with the current state of the art in tissue
engineering, including the fact that generation of a perfused capillary network
in vitro has not yet been demonstrated, the goal of creating an entire new
organ for transplant remains distant. It is thus prudent to focus on addressing
substantial clinical problems that rely on solving single steps. One such
clinical problem is the need to repair and improve contractile function of the
failing heart by local cell implantation or surgical addition of a myocardial
patch.
Another promising area of cardiovascular tissue
engineering involves cardiac valves. Congenital and acquired diseases of the
heart valves and great arteries are leading causes of morbidity and mortality.
Current prosthetic or bioprosthetic replacement devises are imperfect due to
one or more ongoing risks including thrombosis, limited durability, infection,
and the need for re-operations due to lack of growth. Through a
tissue-engineering approach, progress could be made in producing more
physiological valve replacements.
Vasculature
To date, whereas clinical experience with large
diameter vascular grafts (e.g., for aortic aneurysm) has been generally
favorable, no good substitutes exist for small vessels of less than 6 mm
diameter. Small diameter vascular grafts are critical for the treatment of
peripheral vascular and coronary artery disease. Grafts currently in use for
bypass surgery are obtained either from the patients' own vessels or are
constructed of synthetic materials. In either case, problems with vessel
availability and high rates of failure due to thrombosis and occlusion make the
use of these grafts less than optimal. Efforts to develop tissue-engineered
vascular grafts with improved long-term patency have been undertaken. and there
have been some promising developments particularly with the addition of
physiologically relevant mechanical stress to the growing tissue. Long term
performance of such grafts is pending and human performance data are not yet
available.
Blood
A number of important opportunities for clinical
application exist. Although bone marrow, peripheral blood stem cell, and cord
blood stem cell transplants are being carried out in increasing numbers, the
very high rate of morbidity and mortality signal the need for modification of
existing conditions as well as development of new approaches. An overview of
research needs necessary for optimal clinical applications is as follows.
First, the properties of stem cells predictive of successful engraftment are
undefined. Correlation between in vitro assays and in vivo results must be
improved to provide better predictors of clinical outcome. A serious
complication following stem cell transplantation is graft-versus-host disease
(GvHD). GvHD might be reduced if not eliminated by development of methods to
tolerize the recipient with allochimerism. It is also clear that less toxic
conditioning regimens are badly needed. Graft rejection occurs frequently, yet
ways to predict rejection and avoid it are poorly described. Collection of
inadequate numbers of engraftable cells from peripheral blood or umbilical
cords continues to be a problem. Although some modest success in expansion in
culture has been reported, it remains very difficult to produce adequate
numbers of totipotent stem cells without differentiation into unengraftable
progenitors. Much research remains to be done so that adequate numbers of
engraftable stem cells can be produced ex vivo. New approaches may emanate from
recent reports of production of hematopoietic stem cells from neural cells.
Indeed, the plasticity of stem cells exhibited by neural cell differentiation
offers exciting opportunities to manipulate stem cells.
Opportunities for clinical application of these
technologies is tremendous. For example, autoimmune disorders can be
effectively treated by stem cell transplantation. However, wider application of
such therapy is now limited by availability of antigenically compatible stem
cells as well as toxicity of conditioning regimens. Future efforts in bone
marrow transplantation should be directed at broader application. Efforts
should be extended to make allogeneic transplantation more feasible. In
particular, bone marrow transplantation needs to be more cost effective in
order to be available to a wider range of patients. Application in older
patients especially needs to be addressed, as the population grows older and
health among older persons improves in general. Currently, bone marrow as well
as heart, lung and liver transplantation are procedures which are restricted or
discouraged in older patients or in patients with other underlying disease.
These restrictions need to be reevaluated continually, and the limitations
lifted as soon as possible.
Finally, increasingly sophisticated medical therapy
is increasing the need for transfusable blood components. Production of blood
components ex vivo has the potential to minimize reliance on voluntary blood
donation to meet these increasing needs. In the area of red cell replacement,
there is still no alternative for transfusion. However, it is likely that in
the next few years, new oxygen carrying solutions will be developed which can
alleviate up to two-thirds of current transfusions of red blood cells in the
U.S. These products are acellular and therefore have plasma persistence times
measured in days, not weeks. However, there are no plans to provide
alternatives for the other 1/3 of red cell transfusions which are in patients
with chronic disease, or bone marrow failure who require regular transfusions.
Long-term culture of human red blood cells is a possible alternative to
allogeneic red cell transfusion, but presently is limited by inability to
maintain long-term cultures or for prolonged storage of cells produced in
vitro. Beyond improvements in culture conditions and requirements, attention
needs to be directed at massive scale-up. In this regard, industry needs to be
recruited to apply methods which traditional academic researchers are not
familiar with. In addition, platelet usage in the U.S. continues to increase as
cancer treatments intensify and new surgical procedures become available to
more patients. At present there are no promising alternatives to the use of
human platelets in surgical patients who have been significantly hemodiluted or
in other thrombocytopenias. Efforts for in vitro culture of such cells on large
scale, by commercially- viable methods should be encouraged.
Lung
Lung disease often progresses far beyond local tissue
damage and involves the whole organ. For several lung diseases including
emphysema, pulmonary fibrosis, and primary pulmonary hypertension
transplantation is the only current therapy for end stage lung disease.
However, transplantation is constrained by donor availability and, consequently
many patients die awaiting a lung transplant. Therefore, a grave clinical need
to seek alternatives to lung transplantation exists. The lung, however,
probably represents the greatest challenge to tissuegenesis and organogenesis.
It is comprised of a wide variety of highly differentiated cell types organized
in a uniquely complicated architecture. For instance, lung parenchyma, airways,
and the pulmonary vasculature consist of over 40 different cell types.
Moreover, ventilation-perfusion matching is an imperative for function.
Restoration of complex vascular networks must accompany tissue repair.
From lung injury during infancy that results in
bronchopulmonary dysplasia to idiopathic pulmonary fibrosis that occurs in
middle and later years of life, the lung represents an organ whose function
cannot be permanently replaced by any mechanical device as might occur with
mechanical assist devices for heart, such as pacemakers and valves, or for
kidneys, such as routine dialysis. Major disease categories accounting for
replacement needs include pulmonary fibrosis, chronic obstructive pulmonary
disease, cystic fibrosis, pulmonary hypertension and others.
New insights into tissuegenesis of the lung will
likely emerge from an improved understanding of injury and repair. Options for
repair are likely to surface as studies on developmental mechanisms in the lung
continue, particularly in the area of systems engineering, i. e. matching
vascularization with structural replacement. In order to take advantage of
opportunities for intervention, study of normal lung growth and development, as
well as those on repair and regeneration must continue to determine whether
common mechanisms are involved in these processes. Since early developmental
events may be determinative of lung sequelae later in life, information on
fetal lung development as well as post-natal events such as alveolar septation
mechanisms is required. Comparison of differences between factors elaborated
during lung development with those which can be identified as active during
post-pneumonectomy lung growth should provide a guide to deciphering the link
between regeneration and growth of the collateral circulation. Recent work has
shown that pulmonary vascular development requires crosstalk with the
developing epithelium for normal development. Markers of early vasculogenesis
in the developing lung have indicated that endothelial precursor cells are
associated with pulmonary epithelial cells as soon as the lung primordial buds
evaginate from the foregut endoderm. These data indicate that the initiation of
lung epithelial morphogenesis and lung vasculogenesis are synchronized and
appear to be co-dependent processes. It is highly likely that a similar
signaling gradient exists among cell types participating in repair.
It is likely that relatively few cell types play a
pivotal role in development and maintenance of the normal architecture of the
lung. Functional activity of cell types and cell-cell interactions could
provide important information on how the architecture of the lung is
determined. For instance, studies on how specific cell types might propagate
along the highly differentiated matrix of the lung and airways could provide a
model to approach lung construction problems via utilization of endogenous
scaffolding. Although a primordial stem cell may not exist as such in the lung,
opportunities for de-differentiation and subsequent controlled functional
differentiation do, indeed, appear to exist. Expanding knowledge in this area
may permit identification of the most hospitable location for transfer of small
patches to replace function in disease.
The importance of mechanical factors should not be
ignored and the development of natural or synthetic materials for the
manufacture of airway stents should not be overlooked. Likewise, the
opportunity to implant tracheal rings that are vascularized and enervated for
purposes of local repair should be explored. It is likely that the future holds
much promise for a more functional approach to tissue and organ replacement
through tissue engineering methodology. Progress in this area will depend upon
the successful merger of molecular medicine and bio-engineering.
SUMMARY OF
RECOMMENDATIONS
As a result of the Working Group Meeting, the
following recommendations for basic science and technology development, and
clinical areas to be addressed, have emerged.
1. Basic Science and Technology Common to Heart,
Lung, and Blood
Progenitor Cell Biology--Progenitor cell
formation and differentiation including: 1) Development of cellular markers to
distinguish progenitor cells; 2) Location of progenitor cells in the adult; 3)
Understanding growth factors and matrix molecules needed to support their
growth and morphogenesis and; 4) Evaluation of methods to "erase"
differentiation and thereby generate cells capable of becoming progenitor cells
of other tissue.
- Vascularization-- Research in two major
areas is needed: 1) For cells or patches of tissue implanted directly into a
site in vivo, knowledge of the temporal regulation of known molecular players
and signaling hierarchies during development and regeneration of vascular
networks, and mechanisms of vessel regression; 2) For tissues grown in vitro,
ways to create vascular networks ranging from capillaries to arteries/veins
that are capable of anastomosing with vessels at the site of implantation.
- Matrix and Growth Factor Interactions--1)
Understanding what environmental cues, including growth factors and matrix
molecules, attract the cells that ultimately lead to repopulation of sites of
injury and identifying where such cells originate. 2) Understanding the factors
that prevent regeneration of injured structures. 3) Developing quantitative
analyses and modeling of how signals are presented physically and temporally,
and how the cells integrate these multiple overlapping signals to generate a
response which could provide a design basis for the manipulation of the
environment to achieve tissuegenesis.
- Scaffold Fabrication and Control of Cell
Behavior--Techniques for creating scaffolds with complex architecture and
chemistry must be developed significantly beyond current stages to address the
needs of vascularized and innervated tissues.
2. Functional Applications of Science and
Technology to Clinical Problems
- Heart--1) Engineer cardiac cells,
myocardial patches, or total hearts for implantation to restore, renew or
replace the contractile function of the failing heart. 2) Tissue engineer
valves to treat congenital or acquired diseases of the heart valves and great
arteries. 3) Develop physiologic biomechanical environments to optimize
development of engineered cardiac tissues.
- VasculatureFurther efforts to develop
tissue-engineered vascular grafts with improved long-term patency need to be
undertaken particularly with the addition of physiologically relevant
mechanical forces to the growing tissue.
- Blood1) Hematopoietic stem cells:
assays for stem cell products that predict engraftment in patients, transplant
regimens with reduced toxicity, regimens that induce tolerance, methods to
identify, purify, and expand specific populations of lineage committed cells,
and generation of "generic" stem cell populations from bone marrow (i.e.,
mesenchymal stem cells, muscle, liver, etc. 2) Transfusable blood components:
culture-derived red blood cells and platelets (or their precursors), artificial
oxygen carrying solutions, methods to prevent immunization by such cells or
artificial blood components, and large scale production and storage methods are
needed.
- Lung--1) Novel approaches such as using
micro-patches of primordial lung tissue to replace gas exchange areas destroyed
by dysfunctional tissue. 2) Effects of mechanical factors on function of newly
generated or transplanted tissues will need to be assessed.
WORKING GROUP ON TISSUEGENESIS/ORGANOGENESIS OF HEARTS,
BLOOD VESSELS, LUNGS AND BLOOD
Location: Rockledge II, Conference
Room 9116 Date: Friday, August 13, 1999 AGENDA
AM |
Discussion Leader |
8:00 |
Coffee |
|
8:10 |
Welcome and Introductions |
Christine
Kelley |
8:20 |
Opening Remarks |
Christine
Kelley |
8:30 |
Goals and Objectives of
Working Group |
William
Martin Linda Griffith |
8:40 |
Developmental Biology of Stem
Cells, Tissues, and Organs |
Mark
Fishman |
9:40 |
Gene Regulation in Tissues and
Organs |
Peter
Quesenberry |
10:40 |
Break |
|
11:00 |
Structural and Functional
Histoarchitecture |
Marlene
Rabinovitch |
12:00 |
Working Lunch |
|
PM |
1:10 |
Vascularization of Growing
Tissues and Organs |
Patricia
D'Amore |
2:00 |
Response to Injury |
Jeffrey
Whitsett |
3:00 |
Break |
|
3:10 |
Other Topics |
William
Martin Linda Griffith |
3:45 |
Discussion, Recommendations,
Implementation Strategies |
William
Martin Linda Griffith |
4:45 |
Adjourn |
|
ROSTER WORKING GROUP MEETING ON
TISSUEGENESIS/ORGANOGENESIS
Co-Chairs: William J. Martin II,
M.D. Department of Medicine
Indiana University Medical
Center 1001 West 10th Street, OPW 425 Indianapolis, IN
46202-2879 Telephone: (317) 630-8445 Fax: (317) 630-6386 Email:
wjmartin@iupui.edu
Linda
G. Griffith, Ph.D. Div Bioeng & Envrnmt Building 66, Room
466 77 Massachusetts Ave. Cambridge, MA 02139 Telephone: (617)
253-0013 Fax: (617) 258-5042 Email: griff@mit.edu
Participants: Ronald G. Crystal,
M.D. Cornell University Medical College 1300 York Avenue, Box 96
New York, New York 10021 Telephone: (212) 746-2258 Fax: (212)
746-8383 Email: rgcryst@mail.med.cornell.edu
Patricia A.
D'Amore, Ph.D. Schepens Eye Research Institute 20 Staniford
Street Boston, MA 02114 Telephone: (617) 912-2559 Fax: (617)
912-0128 Email: pdamore@vision.eri.harvard.edu
Mark
C. Fishman, M.D. Massachusetts General Hospital Dept. of
Medicine 149 13th St., 4th Floor Charlestown, MA, 02129-2060
Telephone: (617) 726-3738 Fax: (617) 726-5806 Email:
fishman@cvrc.mgh.harvard.edu
Robert Kloner, M.D.
Good Samaritan Hospital Department Of
Heart Institute/Research 1225 Wilshire Boulevard Los Angeles, CA
90017 Telephone: (213) 977-4050 Fax: (213) 977-4107 Email:
rkloner@goodsam.org
Gloria D. Massaro, M.D.
Georgetown University School of
Medicine Lung Biology Laboratory Pre-Clinical Science Bldg.
GM-12 3900 Resevoir Rd. Washington, D.C. 20007 Telephone: (202)
687-4967 Fax: (202) 687-8538 Email:
massarog@gusun.georgetown.edu
David J. Mooney,
Ph.D. Department of Biologic and Materials Science University
of Michigan School of Dentistry 1011 North University Ave. Ann Arbor,
MI 48109-1078 Telephone: (734) 764-2560 Fax: (734) 647-2110 Email:
mooneyd@umich.edu
Peter J. Quesenberry, M.D.
University of Massachusetts Medical
Center Cancer Center 373 Plantation Street Suite 302, Biotech
Two Worcester, MA 01604 Telephone: (508) 856-6958 Fax: (508)
856-1310 Email: quesenbp@ummhc.org
Marlene Rabinovitch, M.D.
The Hospital for Sick Children
University of Toronto 555 University Avenue Toronto, Ontario M5S
1X8 Canada Telephone: (416) 813-5918 Fax: (416) 813-7480 Email:
mr@sickkids.on.ca
Shahin Rafii, M.D. Cornell University Medical
College Department of Hematology/Oncology Room C-606 1300 York
Avenue New York, NY 10021 Telephone: 212-746-2070 Fax:
212-746-8866 Email: srafii@mail.med.cornell.edu
H. Steven
Wiley, Ph.D. University of Utah Dept. of Pathology 50 North
Medical Drive Salt Lake City, UT 84132 Telephone: (801) 581-5967
Fax: (801) 581-4517 Email: wiley@path.med.utah.edu
Jeffrey
A. Whitsett, M.D. Children's Hospital Medical Center Division of
Pulmonary Biology 3333 Burnet Ave. Cincinnati, OH 45229-3039
Telephone: (513) 636-4830 Fax: (513) 636-7868 Email:
whitj0@chmcc.org
Robert M. Winslow, M.D.
Sangart, Inc. 11199 Sorrento Valley
Rd. San Diego, CA 92121 Telephone: (619) 455-0966 Fax: (619)
455-6993 Email: rwinslow@sangart.com
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