The Stem Cell Concept
What is a Stem Cell? A stem cell is a rela5vely undifferen5ated cell that, when it divides produces at least one daughter cell that retains its undifferen5ated character. Thus, a stem cell has the poten5al to make more stem cells self- renew - while also producing cells capable of differen5a5ng in a par5cular manner.
Several organs contain a stem cell popula5on. Stem cells produce progeny cells that include another stem cell a cell commieed to differen5ate into par5cular lineage. These commieed cells give rise to progenitor cells that will eventually differen5ate. Progenitor cells are undifferen5ated cells that are commieed to a par5cular path of differen5a5on.
Example: The hematopoie5c stem cell How were stem cells discovered? Biologists no5ced that, although blood cells were constantly removed by the spleen, there was always an equal number of blood cells produced to replace them. There must be new blood cells produced in the adult body.
Hematopoie5c stem cells Experiment: host mice were lethally irradiated. The lethality associated with irradia5on is because the blood and immune cells are destroyed. Bone marrow was taken from a donor mouse and injected into the irradiated mice. Result: New blood cells developed in the irradiated mice. Different types of blood cells were produced. Transplanted cells could give rise to more blood cells. Conclusion: Blood cells were being replenished AND the blood stem cells were being replenished.
Types of stem cells to3potent cells: can form every cell in the body. In mammals this means all embryonic and extraembryionic cells. Only the zygote and the probably the first 4-8 blastomeres are to5potent in mammals. pluripotent cells: can form most of the cells of the embryo. In mammals the inner cell mass cells are pluripotent because they can no longer produce trophoblast cells.
mul3potent cells: can be in either the embryo or the adult. They can produce a limited number of cell types. An example of a mul5potent stem cell is the hematopoie5c stem cell. These can produce all different types of blood cells, but cannot produce other cell types. unipotent stem cells: produce only a par5cular type of cell. An example is the spermatogonia, the stem cells that give rise to only sperm.
Progenitor cells Progenitor cells are undifferen5ated cells that are derived from stem cells. The differ from stem cells in that they do not have the ability to self- renew. Progenitor cells oxen divide a few 5mes before differen5a5ng. These division produce more progenitor cells all of which differen5ate.
Stem Cell Niches Many adult 5ssues and organs contain stem cells that undergo con5nual renew. examples: epidermis, hair follicles, intes5nal villi, blood cells, sperm cells. How are these stem cells maintained in their undifferen5ated state in adult 5ssues? The stem cells are housed in a regulatory microenvironment called the stem cell niche.
The stem cell niche creates a microenvironment that regulates prolifera5on and differen5a5on via paracrine or juxtacrine factors. The paracrine or juxtacrine factors are produced by the cells that make up the niche. These factors maintain the stem cells in an uncommieed state. Once stem cells leave the niche, these factors can no longer reach them and they begin to differen5ate. A balance must be maintained such that too few or two many stem cells are not produced. Too many stem cells can lead to cancers Too few stem cells lead to loss of the stem cell popula5on promo5ng aging and decay
The Hematopoie5c stem cell niche
The Hematopoie5c stem cell niche Hematopoie5c stem cells produce the different types of blood cells. The hematopoie5c stem cell niche resides in the hollow cavi5es par5cular bones, for example the femur, where the bone marrow is. The niche consists of bone cells (osteoblasts), the cells lining the blood cells and nearby neurons.
The Hematopoie5c stem cell niche A complex cocktail of of paracrine factors, juxtacrine factors, extracellular matrix signaling factors, hormones and neurotransmieers regulates hematopoiesis. Depending on the needs of the body, more red blood cells or more white blood cells can be produced. They type of cells produced is also regulated by the niche.
The Hematopoie5c stem cell niche
The intes5nal Stem Cell Niche
The intes5nal Stem Cell Niche The stem cell niche is within the intes5nal crypts. New stem cells are made within the niche. They move upwards out of the niche, where they can differen5ate into any of the intes5nal cell types.
Intes5nal stem cell niche The Paneth cells make up the stem cell niche. Paneth cells express several paracrine and juxtracrine factors (like Wnt, EGF, and Delta). If Paneth cells are deleted, stem cells are no longer produced, therefore Paneth cells maintain the stem cell popula5on.
Pluripotent Embryonic Stem Cells Pluripotent embryonic cells are special because they can generate all the cell types of the adult body. They can be derived from two sources 1. Cells of the inner cell mass: these generate embryonic stem cells (ES cells). 2. Primordial (undifferen5ated) germ cells: these generate embryonic germ cells (EG cells).
Embryonic stem cells (ES cells) are generated by culturing cells from the inner cell mass. Embryonic germ cells (EG cells) are generated by culturing primordial germ cells from the embryo. The culture media is specialized to maintain ES or EG cells in an undifferen5ated state.
By placing ES or EG cells into culture media consis5ng of different paracrine factors, the cells can be induced to differen5ate into different cell types.
Stem Cell Therapy ES and EG cells can oxen differen5ate into any cell type, even when placed in an adult body. EG cells were able to cure motor neuron injuries in adult rats. They differen5ated into new neurons and also produced paracrine factors that prevented death of exis5ng neurons. Similarly ES cells were also able to cure a Parkinson- like condi5on in adult monkeys.
Stem Cell Therapy Problems with ES or EG cells in stem cell therapy. 1. The ES or EG cells would be derived from a different genotype from the pa5ent and therefore may be rejected by the immune system. 2. Ethical dilemma cells are derived from embryos.
Induced pluripotent stem cells In 2006, a Takahashi and Yamanaka demonstrated that cells of the adult body could be made into pluripotent cells merely by inser5ng four genes. These cells were called induced pluripotent stem cells (ips cells). Further experiments found that it was possible to generate ips cells with a minimum of 3 inserted genes.
ips cells and regenera5ve medicine In animal models, ips cells have been used to cure diseases. For example: sickle cell anemia model.
ips cells and regenera5ve medicine Scien5sts hope that ips cell cell research will lead to the development of cell replacement therapy similar to experiments done in animal models. This type of therapy would poten5ally circumvent the problems of immune rejec5on of donor cells because the cells are derived directly from the pa5ent. However, ips cell research is s5ll young and the safety of such therapy needs further inves5ga5on.
ips cells, disease research and drug development Currently, ips cells are best used for the study of diseases and development of poten5al treatments (i.e. drugs). For Example: studies of cys5c fibrosis.
Mice do not get the same type of cys5c fibrosis as humans. cys5c fibrosis is a gene5c disease that effects mucus producing 5ssues such as the lungs and intes5nes. Therefore, mice could not be used as an animal model that might accurately reflect human disease. Researchers derived ips cells from a cys5c fibrosis pa5ent. The ips cells were then cultured in a way so that they differen5ated into lung epithelium. The epithelial cells demonstrated characteris5cs of human cys5c fibrosis. Studies of these cells may lead to new insights and discovery of new therapeu5cs for cys5c fibrosis pa5ents.
Robinton and Daley 2012
Natural Stem Cell Therapy: Coopera5on between fetus and mother Pluripotent and mul5potent cells have been found in the blood of pregnant mice and women. In humans these cells can leave the mother s blood and integrate into her exis5ng organs. These embryo- derived stem cells may preferen5ally integrate into damaged or diseased organs.