Embryology   Biology 441   Vertebrate Embryology, Spring 2016   Albert Harris


April 25, 2016

Stem Cells


Some differentiated cell types are continually replaced by mitotic division of cells that are already differentiated. Liver cells are an example; so are endothelial cells. Probably cartilage and bone cells are too (& smooth muscles). Those are NOT considered to be stem cells, in that they are already differentiated.

Stem cells get continually replaced by differentiation of cells that had previously not been differentiated.
Examples are
1) (blood) stem cells in bone marrow,
2) (skin) epidermal cells,
3) crypt cells of the intestinal lining, &
4) sperm cell precursors.

Other species have more examples (tooth cells in alligators.) Many species of sea squirts continually replace almost the whole body.

In "bone marrow transplants", the blood-forming stem cells are what matters.
~ 50,000 successful bone marrow transplants per year.
This success gave people the idea of analogous transplants of more kinds of cells.

"Mesenchymal Stem Cells" can be tissue-cultured from mammal bone marrow, umbilical cord blood, and fat tissue. They can differentiate into cartilage, bone, muscle fat and nerves. They are different from the blood-forming bone marrow cells (according to Slack, page 85 of the book cited below, but he isn't sure that they normally replace skeletal or muscle cells in the adult body.) Which cell type they differentiate into is strongly influenced by substratum or matrix flexibility.

If very stiff, --> Bone; Moderately stiff --> Muscle; More flexible --> Nerve. [discovered by Dennis Discher]

New meanings of the term "stem cell": (re-naming as a way to make hypotheses more persuasive) .

Tissue culture cells derived from dissecting inner cell mass cells out of blastocyst stage of mammal embryos. ("Embryonic stem cells")

Previously differentiated tissue culture cells into which viruses were used to add extra genes for certain transcription factor genes. This causes cells to lose their differentiation (temporarily?).
(The resulting undifferentiated cells are called "Adult stem cells")
[Sox2, Klf4, and Myc Dr. Shinya Yamanaka of Kyoto University 2006]

The morality debates have been mostly about the embryonic stem cells. (Many people don't know they are different.) Extending the meaning of "stem cells" supports hypotheses that those other kinds of cells can be as successfully transplanted: Maybe nerve cells to treat Parkinson's Disease and skeletal muscle cells to treat muscular dystrophy.

"Regenerative Medicine" has become a hot topic. Their annual research meeting was at Hilton Head a month ago.

Jonathan Slack has recently published a book "Stem Cells: A Very Short Introduction" eleven dollars
(I highly recommend it)
Besides being scientifically excellent, this book has a very sardonic sense of humor; for example:

Page 40 "The main demand for human reproductive cloning, were it ever to become practical, is not from dictators who wish to create vast armies of loyal automatons (these are readily available anyway)...

Page 81 "There is a method of observing slow cell turnover in humans. It relies on the fact that in the 1950s and early 1960s the governments of the USA, USSR, Britain and France carried out an extensive radio-labeling experiment on the entire population of the world without their consent. "

Page 103: We live in a world where money can be acquired by attracting attention and by making promises. The hype has been further amplified by the ethical debate over human embryonic stem cells which led the proponents of stem cell research to promise very rapid development of very radical cures.

Nowhere has the hype been greater than California where the California Institute for Regenerative Medicine (CIRM) was set up using three billion dollars of public money raised from state bonds. The motivation was an attempt to circumvent the federal funding restrictions introduced by President Bush in 2001. California is always pleased to do things that annoy Washington. As a result of all the blandishments, the California public really believes that new cures will come in just a few years and the politicians really believe they will get their money back in taxes from new profitable companies built on the technology. The scientists tend to be somewhat less optimistic in private than they are in public. Some of those who work with human pluripotent stem cells do not think that there will ever be cell therapies based on their use.

Slack also refers "stem cell tourism" and "aspirational stem cells", meaning untested methods that might possibly work, but haven't really been tested.


Some comments of my own:

Notice that bone marrow cells can find their own way back to the marrow, and don't need to be put in some particular location or geometric arrangement in order to function.
Would that also be true for muscle cells, skeletal cells, nerve cells? Maybe.

Actually, pancreatic beta cells really do reposition themselves after transplantation.


Why should replacement of muscle cell or nerve cells require de-differentiated cells? Wouldn't it be just as good to get tissue cultures of dividing muscle cells or nerve cell precursors.

The "stem-ness" of replacement cells is irrelevant. Just because bone marrow has undifferentiated stem cells give people an irrational expectation that lack of differentiation is, for some unknown reason, needed for cells to reproduce in culture and/or to organize into functional structures in the body.

Salamander leg regeneration works by growth and rearrangement of cartilage, muscle and other cell types. Although these cartilage and muscle cells seem to de-differentiate, they always revert to become the same cell type.


A very important discovery by Dennis Discher is the flexibility of tissue culture substrata can control which cell type cells differentiate into at differentiation.

Science. 2005 Nov 18;310(5751):1139-43. Tissue cells feel and respond to the stiffness of their substrate. Discher DE, Janmey P, Wang YL.

Cell. 2006 Aug 25;126(4):677-89. Matrix elasticity directs stem cell lineage specification. Engler AJ, Sen, S. Sweeney HL Discher, DE

Microenvironments appear important in stem cell lineage specification but can be difficult to adequately characterize or control with soft tissues. Naive mesenchymal stem cells (MSCs) are shown here to specify lineage and commit to phenotypes with extreme sensitivity to tissue-level elasticity. Soft matrices that mimic brain are neurogenic, stiffer matrices that mimic muscle are myogenic, and comparatively rigid matrices that mimic collagenous bone prove osteogenic. During the initial week in culture, reprogramming of these lineages is possible with addition of soluble induction factors, but after several weeks in culture, the cells commit to the lineage specified by matrix elasticity, consistent with the elasticity-insensitive commitment of differentiated cell types. Inhibition of non-muscle myosin II blocks all elasticity-directed lineage specification-without strongly perturbing many other aspects of cell function and shape. The results have significant implications for understanding physical effects of the in vivo microenvironment and also for therapeutic uses of stem cells.


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