jasna marinović, m.d., ph.d. associate professor department of physiology

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Cell Biology Lecture Stem Cells Jasna Marinović, M.D., Ph.D. Associate Professor Department of Physiology

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Cell Biology Lecture Stem Cells

Cell Biology Lecture Stem CellsJasna Marinovi, M.D., Ph.D.Associate ProfessorDepartment of PhysiologyKey ConceptsWhat are stem cells?What are different types of stem cells and where do they come from?What is the potential for new medical treatments using stem cells?What are stem cells?unspecialized cells capable of renewing themselves through cell division.But, under certain conditions, stem cells can be induced to differentiate into another, tissuse- or organ-specific cell type.Stem cells are unspecialized, non-differentiated cells capable of renewing themselves through cell division.3Embryonic development

In fact, an organizam, including human develops from a single fertilized egg by two main processes:A growth a simple division of cells first, unspecialized, totipotent embrionic stem cells as shown above.And a differentiation a specialization of cell, where they take up tissue-specific functions.4Historic perspective

Differentiation was for long time disregarded, and for centuries it was believed that a human develops from a homunculus, all squashed together in the sperm head, and that the organizam develops only by growth.5

Blastocyst

Differentiation is a gradual process. After egg fertilization, the cells divide as they travel down the Fallopian tube, an just before the implantation into the uterine wall, a blastocyst is formed. Inside the blastocyst there is accumulation of cells which is called inner cell mass, that will form later the embryo, and from the surrounding cells, the placenta will form. The inner cells mass will then form three germ layers: endoderm, mesoderm and ectoderm.7Germ layers

Differentiation is gradual

Differentiation is gradual and is achieved through many steps and this is example how the beta cell in pancreatic islet becomes itself through several stages. Differentiation is achieved through turning on and off at different times various genes. These genes are regulated by both intracellular (cytoplasmic) factors and cell-to-cell interactions.9As differentiation reaches its end, the stem cells become very sparse

10Body renewal - maintenance

The remaining stem cells are responsible are in part for the body renewal and maintenance, meaning that, atlhough we may feel the same and look the same, our cells are constantly changing.

11Stem cells

Hematopoetic stem cells

One of the best known and understood stem cells is heamtopoetic stem cell of the bone marrow, which can differentiate into any type of blood cell. This is used clinically in bone-marrow transplants.13

Even a single hematopoetic stem cell can replenish the blood in mouse. This is used clinically in bone-marrow transplants in patients after transplantation.But some organs replenish themselves not using stem cells but rather simple division of already differentiated cells. One example is beta cells in Pancreatic islets. The significance of it is that if the fully differentiated cell is lost, there is no other resource to make up for the loss example is DM type I.

14Types of stem cells

15Embrionic stem (ES) cells

Inner mass from the blastocyst is dissected out and put into culture dish on a feeder layer of cells (usually mouse embryonic fibroblasts) Some of the inner mass cells will become stem cells and continue growing and dividing and make lines of embrionic stem cells that can divide in culture indefinitely. By changing conditions (adding various growth factors), we can direct differentiation into a certain cell type. But, without adding GFs, the cells will differentiate spontaneously.16ES cells can differentiate into any tissue

Chimeric mouse, a mouse derived from two animals, is a proof that ES cells can differentiate in any tissue. ES cells from the brown-coat mouse were injected into blastocyst,of a white coat mouse. A spotted animals was born having combination of cells from both animals.17Human embryonic stem cells

Human embrionic stem cells were derived from blastocysts that were made before by IVF, left frozen in fertility clinics and otherwise would be discarded. They were taken after inormed consent of the patients they originated from. The techinque for isolation and growing of hES cells originated from Dr. Thomson in 1998 at UW-Madison.18Adult stem cells

EmbyonicAdultMost potentialCan form all cell typesImmortal in culturePlentifulOrgan-specificCan form few cell typesLimited life-span (in culture)Hard to isolateAdult stem cellsFirst identified only in bone marrow (hematopoetic - producing blood elements; and stromal stem cells producing bone, cartilage, fat).In 1990s, identified in heart, brain, blood vessels, skeletal muscle, gut, liver, ovaries, testis.Very sparse, quiescent and activated only after injury.Insufficient to enable organ regeneration.Induced Pluripotent Stem Cellsgenetically reprogrammed adult cells to assume embryonic stem-cell phenotype - dedifferentiationGenerated in 2006.Viruses used to introduce reprogramming-genes into adult cellsLimitation: danger from metastatic cancer (Potential)Applications of Stem cellsTesting new medications on differentiated cells from human pluripotent stem cell linesCell-based therapies Source of replacement cells for repair of terminally damaged tissues (nerve cells, heart cells)Tissue and organ engineering in vitroUse of stem cells in heart disease Cardiac transplant currently the only therapy for advanced heart failure too few donor hearts. Cardiomyocytes proliferation after birth extremely rare turnover rate 1 % /year (young adults). First studies in mice transplanted with skeletal myoblasts were promising human trials

Milestones in clinical trials of cardiac regeneration therapies(Lancet 2012;379:933-42)

Lancet 2012;379:933-42Engineering whole organs and complex tissues Ultimate goal, replacing the need for donor organs (insufficient). Necessary: Biological scaffold of extracellular matrix (template for tissue reconstruction) Appropriate autologous stem cells or differentiated cells Successful examples in humans: trachea, oesophagus, skeletal muscleEngineered airway

Clinical transplantation of a tissue-engineered airway Lancet 2008; 372; 2023-30.