| 1 |
Introduction |
Getting to know each other.
Course overview.
Literature and database searches.
An introduction to the field of regenerative medicine. |
| 2 |
An Introduction to Stem Cells |
We will begin the class by discussing differences between embryonic, fetal, cord blood, placental and adult stem cells. First, we will analyze a landmark paper about isolating pluripotent cells from mouse embryos. Afterwards, we will discuss a recent paper about reprogramming adult fibroblasts into pluripotent cells, which can bypass ethical dilemmas about the use of embryos. |
| 3 |
Molecular and Cellular Bases of Organ Development |
Tissue is normally generated during fetal development by a complex interplay among multiple molecular and cellular mechanisms leading to the differentiation of stem cells. These mechanisms are based on cell communication by conserved families of signaling molecules, such as Dpp/BMP, TGF-β, Wnt, FGF, Nodal and Hedgehog. We will study a paper about the effect of Vg1, a member of TGF-β superfamily, on fetal development. The mechanisms of embryonic development are repeated later, in adult life, for tissue regeneration and can be studied in vitro to identify the potential treatments of damaged tissues. The role of eight growth factors on the differentiation of stem cells in vitro will be discussed. |
| 4 |
Cloning of Somatic Cells by Nuclear Transfer |
Somatic cell nuclear transfer is based on replacing the nucleus of an unfertilized egg cell with the nucleus of a somatic cell. If these cloned cells are then placed in the uterus of a female mammal, in a rare instance a cloned organism, like the sheep Dolly, can develop. We will analyze the groundbreaking paper about nuclear transplantation. Then, we will study the cellular mechanisms involved in the cloning of animals and how Scottish researchers produced the sheep Dolly using the nucleus of a mammary gland cell from an adult sheep. |
| 5 |
Therapeutic Uses of Stem Cells |
Stem cells can be used to treat different diseases. The most extensive application to date involves bone marrow stem cell transplantation for the treatment of leukemias and other myeloproliferative disorders. We will discuss studies of bone marrow transplantation in mice and humans and compare different approaches and experimental designs in preclinical and clinical studies. |
| 6 |
Studies of Patients Treated with Stem Cells |
Therapeutic applications of stem cells will be further discussed using meta-analysis, which compares all of the clinical studies conducted on patients suffering from non-malignant diseases, such as autoimmune, cardiac, or vascular diseases, treated with bone marrow and blood-derived stem cells. A video linked to this paper will also be critiqued. To contrast with the meta-analysis, a case report from the field of therapeutic use of bone marrow will be discussed. Instructions for completing the midterm assignment will be provided. |
| 7 |
Visit to the Massachusetts General Hospital |
We will visit Massachusetts General Hospital (MGH) hematology-oncology to see patients after bone marrow transplantation. We will meet there the authors of papers about homing and self-renewal of haematopoietic stem cells and discuss their results. We will discuss the paper about the effect of Galpha signaling on homing and the engraftment of bone marrow. Then, we will analyze the effect of Wnt signaling on self-renewal of hematopoietic stem cells. The trip will consist of 30 min. of a physician presentation, a 30 min. tour, and 1 hour of discussion. |
| 8 |
Molecular Bases of Disease |
The same molecules involved in tissue development can be involved in disease. We will study two examples: chondrodysplasia, a genetic skeletal disorder resulting in arrested development and deformity of limbs, and colon cancer. First, we will analyze the effects of mutations of cartilage-derived morphogenetic protein 1, a member of the TGF-β superfamily, on development of chondrodysplasia. Then, we will study the effect of aberrant Wnt/beta-catenin signaling on colon adenoma formation. |
| 9 |
In vivo Regeneration of Tissues by Cell Transplantation |
In addition to treating bone marrow diseases, adult stem cells can be used to regenerate organs. Mesenchymal stem cells can regenerate cartilage, a promising approach to treating osteoarthritis. As another example of organ regeneration, we will discuss the treatment of myocardial infarctions using bone marrow cells introduced via a catheter placed into the infarct-related artery. |
| 10 |
IPS Cells as Experimental Models of Neurological Disorders |
Human induced pluripotent stem (IPS) cells can be used in vitro with various differentiation factors to model abnormal cells seen in neurological diseases. We will study one such disease - spinal muscular atrophy, a neuromuscular disease characterized by degeneration of motor neurons and resulting in progressive muscular atrophy. We will discuss a paper that describes generation of IPS cells from skin fibroblasts taken from a patient with spinal muscular atrophy. These IPS cells generate defective motor neurons that recapitulate aspects of the disease, which can then be analyzed experimentally. IPS cells might also be used therapeutically, e.g. to improve neuronal function by regulation of microenvironment. We will discuss a paper in which human mesenchymal stromal cells were injected into the hippocampus of adult mice and were able to improve neurologic function and decrease neuronal cell death. |
| 11 |
Bioartificial Organs |
Bioartificial organs combine physical aspects of biological or artificial skeleton and biological aspects of dividing cells. Living cells are usually enclosed in a synthetic envelope. Two examples of bioartificial organs will be discussed. A beating heart was produced using extracellular matrix architecture and cardiac and endothelial cells. Bioartificial kidney was produced using synthetic membranes and tubular cells. |
| 12 |
Tissue Regeneration Driven by Growth Hormones |
The concept of tissue regeneration driven by growth factors that affect stem cells and mimic developmental processes in adult life will be introduced using the example of bone morphogenetic proteins (BMPs). BMPs were discovered by their ability to generate new bone at ectopic sites. The first paper reporting this phenomenon will be discussed. 40 years following that discovery, BMPs won in clinical trials for bone regeneration. One clinical study showing the effect of BMP-7 in the treatment of tibial nonunions, bone fractures that would not heal spontaneously, will be discussed. |
| 13 |
Field Trip to Genzyme |
Genzyme is a large biopharmaceutical company that conducts the research concerning stem cells and produces drugs used in tissue regeneration. We will visit facility that produces drugs, after they have been proven effective and safe in preclinical and clinical trials. The trip will consist of a 20 min. talk by a Genzyme Vice President, a 30 min. tour of the drug production facility, a 30 min. tour of the company and 30 min. of discussion. |
| 14 |
Student Paper Presentations and Discussions |
Students will individually present a paper related to the topics of the course. During each presentation and afterwards, there will be a class discussion. |
