Mesenchymal Stem Cells: A Diverse Family, Large and Still Growing
Perhaps containing more different cell types than any other stem cell category, mesenchymal stem cells (MSCs) can be isolated from a wide variety of tissues in the human body. These cells have been grouped and labeled as “mesenchymal” because they are thought to have a common progenitor in the mesenchyme, an embryonic tissue (Caplan, 2005). In the developing vertebrate embryo, there are three distinct “germ layers,” or layers of cells: the endoderm, the mesoderm, and the ectoderm. Together with the germ cells, these three layers pattern out the entire body (see figure). The mesenchyme is a collection of cells mostly derived from the mesoderm that later becomes supportive structures throughout the body, including bone, cartilage, connective tissue, smooth muscle, adipose tissue, as well as the lymphatic and hematopoietic systems. Most MSCs are thought to contain progenitors in the mesenchyme (Gilbert, 2003; Conrad et al., 2009; Caplan, 2005).
The endoderm layer later becomes skin (epidermis) and the nervous system, the ectoderm becomes the digestive tract and respiratory system, and the mesoderm becomes bone, blood, muscles, connective tissue, and several organs (heart, kidney, and gonads).
However, calling MSCs “mesenchymal” can be misleading. Because this term refers to a precursor of the large MSC family, it is referring to an embryonic tissue, though the descendant MSCs can be found in both fetal and adult tissues. MSCs have been isolated from adult muscle, bone marrow, adipose tissue, cartilage, bone, potentially teeth (Caplan, 2005) as well as some fetal tissues (fetal liver, lung, amniotic fluid, and umbilical cord) (Phinney and Prockop, 2007). The MSCs isolated from any one of these tissues are multipotent and are usually shown to be MSCs by being able to differentiate into at least three different, standard mesenchymal cell types: osteocytes (bone), chondrocytes (cartilage), and adipocytes (fat) (Baksh et al., 2004). There is much evidence, though somewhat inconsistent, showing that MSCs can also differentiate into neuronal cells, which may be from mesenchyme derived from the endoderm instead of the mesoderm (Gilbert, 2003; Phinney and Prockop, 2007). Overall, MSC differentiation potentials can vary depending on what mesenchyme-derived tissue the MSCs were harvested from (Phinney and Prockop, 2007). However, MSCs cannot become hematopoietic cells (which are derived from hematopoietic stem cells), even though these cells are derived from the mesenchyme, making the label “mesenchymal” more deceptive (Gilbert, 2003; Caplan, 2005).
Though MSCs have a relatively long history, only recently have they been fully recognized as a valid stem cell family and their presence in a large array of tissue types discovered. From the 1960s to 1970s, MSCs were mainly studied from bone marrow and cartilage and mostly characterized in model organisms (Friedenstein et al., 1974; Caplan, 2005; Bianco et al., 2008). Specifically, in the 1970s Friedenstein’s group discovered that certain cells isolated from bone marrow can create clonal colonies all descendent from one original cell, and, furthermore, the colonies derived from the single cell precursor can become multiple different cell types (Friedenstein et al., 1974; Bianco et al., 2008). However, because hematopoietic stem cells were already a known stem cell population residing in bone marrow, it was many years before MSCs were widely accepted as a second stem cell population within the bone marrow. The term “mesenchymal stem cell” was later coined in 1991 by Arnold Caplan, but not widely used until 1999, though, as discussed above, its appropriateness is still in question (Bianco et al., 2008). In the 1990s progress was made using human MSCs in optimizing preservation and isolation of these cells, as well as trials in regenerative medicine. Just in the last decade, it has been found that MSCs can be isolated from skeletal muscle, adipose tissue, umbilical chords, the circulatory system, potentially dental pulp, amniotic fluids, and fetal tissues (Phinney and Prockop, 2007).
To improve future MSC applications, standardization of practices is important, and a full understanding of their potential uses in regenerative medicine is essential. Though MSCs are made up of a wide variety of cell types, most share some common proteins expressed on their cell surface that can classify them as a MSC in an assay, to some degree. However, there are no standard isolation methods for MSCs and the harvested populations, which are themselves quite heterogeneous, vary depending on the donor (Phinney and Prockop, 2007). Despite the apparent need for standardization, MSCs are becoming increasingly important in the field of regenerative medicine, having great potential for tissue repair. Specifically, MSCs have properties that inhibit inflammation and immune responses, making them ideal for this field (Phinney and Prockop, 2007). As set protocols are put into place and the large family of MSCs continues to be better understood, MSCs hold the promise of being major players in the future world of regenerative medicine.
References
Baksh, D., Song, L., Tuan, R. S. Adult mesenchymal stem cells: characterization, differentiation, and application in cell and gene therapy. J. Cell. Mol. Med. 2004. 8(3): 301-16.
View ArticleBianco, P., Robey, P. G., Simmons, P. J. Mesenchymal Stem Cells: Revisiting History, Concepts, and Assays. Cell Stem Cell. 2008. 2(4): 313-9.
View ArticleCaplan, A. I. Review: Mesenchymal Stem Cells: Cell–Based Reconstructive Therapy in Orthopedics. Tissue Eng. 2005. 11(7-8): 1198-211.
View ArticleConrad, C., Niess, H., Huss, R., Huber, S., von Luettichau, I., Nelson, P. J., Ott, H. C., Jauch, K., Bruns, C. J. Multipotent Mesenchymal Stem Cells Acquire a Lymphendothelial Phenotype and Enhance Lymphatic Regeneration In Vivo. Circulation. 2009. 119: 281-9.
View ArticleFriedenstein, A. J., Deriglasova, U. F., Kulagina, N. N., Panasuk, A. F., Rudakowa, S. F., Luria, E. A., Ruadkow, I. A. Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp. Hematol. 1974. 2(2): 83–92.
View ArticleGilbert, Scott F. (2003). Developmental Biology, Seventh Edition. Sunderland: Sinauer Associates Inc.
Phinney, D. G. and Prockop, D. J. Concise Review: Mesenchymal Stem/Multipotent Stromal Cells: The State of Transdifferentiation and Modes of Tissue Repair – Current Views. Stem Cells. 2007. 25:2896-902.
View ArticleOriginal “The Three Germ Layers” image from the Wikimedia Commons and redistributed freely as it is in the public domain.
Mesenchymal Stem Cells © 2009-2010, Teisha Rowland. All rights reserved.
Follow on Twitter
thanks for the post… very informative.
If you happen to know of any therapies that have been conducted on humans specifically using MSCs, I’d be very interested to know about this.
Best regards,
Stefan
Hi, Stefan. Thank you for the comment. That is a good point to raise as much work with stem cells has been done in models and has yet to make its way to clinical studies in humans.
The U.S. National Institutes of Health (NIH) actually has a website that lists clinical trials going on worldwide (http://clinicaltrials.gov). Doing a search for mesenchymal stem cells, I found 82 reported studies (though many are not in the U.S.). There are a wide variety of clinical studies going on with mesenchymal stem cells, including treating diabetes, multiple sclerosis, graft-versus-host disease, and many more.
There is also a helpful review on this subject that came out last year which goes into more technical details:
Klingemann, H., Matzilevich, D., Marchand, J. Mesenchymal Stem Cells – Sources and Clinical Applications. Transfus Med Hemother. 2008. 35:272–277.
View Article
Thank you for reading and for the insightful point raised! I hope this helps answer your query.
Human MSCs are being evaluated in a large number of clinical trials for a variety of indications. Initially, the cells were used to treat brittle bone diseases with reasonable success. Most recenlty, their ability to block inflammation and modulate immune cell function is being specifically exploited in clincial trials. Several phase I and II trials have demonstrated real efficacy in treating graft versus host disease and acute kidney failure. Most recenlty, several phase I trails have evaluated MSCs for treatment of stroke. The next few years should see a wealth of new clincial data forthcoming, which may lead to real advances in stem cell-based therapeis. @stefan
@stefan
Thank you for such a thorough, informative comment! I’m honored to have an expert, professor of mesenchymal stem cells give feedback on these cells and their recent, cutting-edge clinical applications. Thank you!
Umbilical cord blood from newborn babies can be used to produce embryonic-like cells that can potentially treat diseases and debilitating conditions.
Now it is possible to differentiate cord blood cells into a type of lung cell. These cells help to repair the airway in lungs after injury. This is a significant discovery because until now the use of brain stem cells was the only way to conduct viable research of this type. In the future, researchers might be able to examine cord blood from babies with lung diseases such as cystic fibrosis and develop better treatments. They will be able to work with umbilical cord blood cells to better understand lung development and to test new drugs.
Mesenchymal stem cells obtained from full-term umbilical cord blood can potentially be used to repair tissue and develop bone and cartilage. As a result, patients can recover faster, thus preventing kidney complications arising from tissue damage. These findings bring new hope to those who suffer from acute kidney failure, a life threatening condition. Acute renal failure occurs when the kidneys are unable to get rid of waste and urine.
Lupus is a disease that affects more than 1.5 million Americans. It is an inflammatory disease that affects the skin, joints and kidneys. Lupus can be life threatening when it attacks major organs such as the kidneys. Stem cell transplant is used to treat patients with severe lupus. In a study of 50 patients who underwent stem cell transplant at Northwestern Hospital in Chicago, 50 percent were free from the disease after five years. The overall survival rate is 84%. Stem cell transplantation offers a ray of hope to lupus sufferers who have failed conventional treatments.
Cord blood stem cell overcomes most of the problems associated with embryonic stem cell research. The latter comes under much scrutiny and debate. It is hard to obtain sufficient stem cells from embryos and the right tissue type for a patient. Cord blood stem cells can be produced and there is more likelihood of finding the right tissue type given a birth rate of 100 million babies a year worldwide.
Cord blood stem cell transplant is becoming increasingly important for treatment of life-threatening diseases and debilitating conditions. Umbilical cord blood stem cells are less prone to rejection than bone marrow or peripheral blood stem cells.