Mesenchymal stem cell
|Mesenchymal stem cell|
|Latin||Cellula mesenchymatica praecursoria|
Mesenchymal stem cells, or MSCs, are multipotent stromal cells that can differentiate into a variety of cell types, including: osteoblasts (bone cells), chondrocytes (cartilage cells), myocytes (muscle cells) and adipocytes (fat cells). This phenomenon has been documented in specific cells and tissues in living animals and their counterparts growing in tissue culture.
While the terms mesenchymal stem cell and marrow stromal cell have been used interchangeably, neither term is sufficiently descriptive:
- Mesenchyme is embryonic connective tissue that is derived from the mesoderm and that differentiates into hematopoietic and connective tissue, whereas MSCs do not differentiate into hematopoietic cells.
- Stromal cells are connective tissue cells that form the supportive structure in which the functional cells of the tissue reside. While this is an accurate description for one function of MSCs, the term fails to convey the relatively recently discovered roles of MSCs in the repair of tissue.
- Because the cells, called MSCs by many labs today, can encompass multipotent cells derived from other non-marrow tissues, such as placenta, umbilical cord blood, adipose tissue, adult muscle, corneal stroma or the dental pulp of deciduous baby teeth, yet do not have the capacity to reconstitute an entire organ, the term multipotent stromal cell has been proposed as a better replacement.
The youngest, most primitive MSCs can be obtained from the umbilical cord tissue, namely Wharton's jelly and the umbilical cord blood. However the MSCs are found in much higher concentration in the Wharton’s jelly compared to the umbilical cord blood, which is a rich source of hematopoietic stem cells. The umbilical cord is easily obtained after the birth of the newborn, is normally thrown away, and poses no risk for collection. The umbilical cord MSCs have more primitive properties than other adult MSCs obtained later in life, which might make them a useful source of MSCs for clinical applications.
An extremely rich source for mesenchymal stem cells is the developing tooth bud of the mandibular third molar. While considered multipotent, they may prove to be pluripotent. The stem cells eventually form enamel, dentin, blood vessels, dental pulp, and nervous tissues, including a minimum of 29 different unique end organs. Because of extreme ease in collection at 8–10 years of age before calcification, and minimal to no morbidity, they will probably constitute a major source for personal banking, research, and multiple therapies. These stem cells have been shown capable of producing hepatocytes.
Adipose tissue is one of the richest sources of MSCs. There are more than 500 times more stem cells in 1 gram of fat than in 1 gram of aspirated bone marrow. Adipose stem cells are actively being researched in clinical trials for treatment of a variety of diseases.
The presence of MSCs in peripheral blood has been controversial. However, a few groups have successfully isolated MSCs from human peripheral blood and been able to expand them in culture. Australian company Cynata also claims the ability to mass-produce MSCs from induced pluripotent stem cells obtained from blood cells using the method of K. Hu et al.
Mesenchymal stem cells are characterized morphologically by a small cell body with a few cell processes that are long and thin. The cell body contains a large, round nucleus with a prominent nucleolus, which is surrounded by finely dispersed chromatin particles, giving the nucleus a clear appearance. The remainder of the cell body contains a small amount of Golgi apparatus, rough endoplasmic reticulum, mitochondria, and polyribosomes. The cells, which are long and thin, are widely dispersed and the adjacent extracellular matrix is populated by a few reticular fibrils but is devoid of the other types of collagen fibrils.
The International Society for Cellular Therapy (ISCT) has proposed a set of standards to define MSCs. A cell can be classified as an MSC if it shows plastic adherent properties under normal culture conditions and has a fibroblast-like morphology. In fact, some argue that MSCs and fibroblasts are functionally identical. Furthermore, MSCs can undergo osteogenic, adipogenic and chondrogenic differentiation ex-vivo. The cultured MSCs also express on their surface CD73, CD90 and CD105, while lacking the expression of CD11b, CD14, CD19, CD34, CD45, CD79a and HLA-DR surface markers.
MSCs have a great capacity for self-renewal while maintaining their multipotency. Beyond that, there is little that can be definitively said. The standard test to confirm multipotency is differentiation of the cells into osteoblasts, adipocytes, and chondrocytes as well as myocytes and neurons. MSCs have been seen to even differentiate into neuron-like cells, but there is lingering doubt whether the MSC-derived neurons are functional. The degree to which the culture will differentiate varies among individuals and how differentiation is induced, e.g., chemical vs. mechanical; and it is not clear whether this variation is due to a different amount of "true" progenitor cells in the culture or variable differentiation capacities of individuals' progenitors. The capacity of cells to proliferate and differentiate is known to decrease with the age of the donor, as well as the time in culture. Likewise, whether this is due to a decrease in the number of MSCs or a change to the existing MSCs is not known.
Numerous studies have demonstrated that human MSCs avoid allorecognition, interfere with dendritic cell and T-cell function, and generate a local immunosuppressive microenvironment by secreting cytokines. It has also been shown that the immunomodulatory function of human MSC is enhanced when the cells are exposed to an inflammatory environment characterised by the presence of elevated local interferon-gamma levels. Other studies contradict some of these findings, reflecting both the highly heterogeneous nature of MSC isolates and the considerable differences between isolates generated by the many different methods under development.
The majority of modern culture techniques still take a colony-forming unit-fibroblasts (CFU-F) approach, where raw unpurified bone marrow or ficoll-purified bone marrow Mononuclear cell are plated directly into cell culture plates or flasks. Mesenchymal stem cells, but not red blood cells or haematopoetic progenitors, are adherent to tissue culture plastic within 24 to 48 hours. However, at least one publication has identified a population of non-adherent MSCs that are not obtained by the direct-plating technique.
Other flow cytometry-based methods allow the sorting of bone marrow cells for specific surface markers, such as STRO-1. STRO-1+ cells are generally more homogenous, and have higher rates of adherence and higher rates of proliferation, but the exact differences between STRO-1+ cells and MSCs are not clear.
The supplementation of basal media with fetal bovine serum or human platelet lysate is common in MSC culture. Prior the use of platelet lysates for MSC culture, the pathogen inactivation process is recommended to prevent pathogen transmission.
Mesenchymal stem cells have been shown to contribute to cancer progression in a number of different cancers, particularly the hematological malignancies because they contact the transformed blood cells in the bone marrow.
The mesenchymal stem cells can be activated and mobilized if needed. However, the efficiency is very low. For instance, damage to muscles heals very slowly but further study into mechanisms of MSC action may provide avenues for increasing their capacity for tissue repair.
Many of the early clinical successes using intravenous transplantation have come in systemic diseases like graft versus host disease and sepsis. However, it is becoming more accepted that diseases involving peripheral tissues, such as inflammatory bowel disease, may be better treated with methods that increase the local concentration of cells. Direct injection or placement of cells into a site in need of repair may be the preferred method of treatment, as vascular delivery suffers from a "pulmonary first pass effect" where intravenous injected cells are sequestered in the lungs. Clinical case reports in orthopedic applications have been published, though the number of patients treated is small and these methods still lack rigorous study demonstrating effectiveness. Wakitani has published a small case series of nine defects in five knees involving surgical transplantation of mesenchymal stem cells with coverage of the treated chondral defects.
- In treating autoimmune disease
At least 218 clinical trials investigating the efficacy of mesenchymal stem cells in treating diseases have been initiated - many of which being autoimmune diseases. Promising results have been shown in a variety of conditions, such as graft versus host disease, Crohn's disease, multiple sclerosis, systemic lupus erythematosus, and systemic sclerosis. While their anti-inflammatory/immunomodulatory effects appear to greatly ameliorate autoimmune disease severity, the durability of these effects remain to be seen.
- Clinical trials of cryopreserved MSCs
Scientists have reported that MSCs when transfused immediately within few hours post thawing may show reduced function or show decreased efficacy in treating diseases as compared to those MSCs which are in log phase of cell growth, so cryopreserved MSCs should be brought back into log phase of cell growth in in vitro culture before these are administered for clinical trials or experimental therapies, re-culturing of MSCs will help in recovering from the shock the cells get during freezing and thawing. Various clinical trials on MSCs have failed which used cryopreserved product immediately post thaw as compared to those clinical trials which used fresh MSCs.
In 1924, Russian-born morphologist Alexander A. Maximow used extensive histological findings to identify a singular type of precursor cell within mesenchyme that develops into different types of blood cells.
Scientists Ernest A. McCulloch and James E. Till first revealed the clonal nature of marrow cells in the 1960s. An ex vivo assay for examining the clonogenic potential of multipotent marrow cells was later reported in the 1970s by Friedenstein and colleagues. In this assay system, stromal cells were referred to as colony-forming unit-fibroblasts (CFU-f).
The first clinical trials of MSCs were completed in 1995 when a group of 15 patients were injected with cultured MSCs to test the safety of the treatment. Since then, over 200 clinical trials have been started. However, most are still in the safety stage of testing.
Subsequent experimentation revealed the plasticity of marrow cells and how their fate could be determined by environmental cues. Culturing marrow stromal cells in the presence of osteogenic stimuli such as ascorbic acid, inorganic phosphate, and dexamethasone could promote their differentiation into osteoblasts. In contrast, the addition of transforming growth factor-beta (TGF-b) could induce chondrogenic markers.
Application in Therapy
Statistical-based analysis of MSC therapy for osteo-diseases inferred that most studies are still under investigation. There are different follow-up times that indicate we are still far from reaching the final conclusion. 
- Nardi, N. Beyer; da Silva Meirelles, L. (2006). "Mesenchymal Stem Cells: Isolation, In Vitro Expansion and Characterization". In Wobus, Anna M.; Boheler, Kenneth. Stem Cells. Handbook of experimental pharmacology 174. pp. 249–82. doi:10.1007/3-540-31265-X_11. ISBN 978-3-540-77854-7.
- Oni OO (1992). "Early histological and ultrastructural changes in medullary fracture callus". J Bone Joint Surg Am 74 (4): 633–4. PMID 1583062.
- Brighton CT, Hunt RM (1997). "Early histologic and ultrastructural changes in microvessels of periosteal callus". J Orthop Trauma 11 (4): 244–53. doi:10.1097/00005131-199705000-00002. PMID 9258821.
- Pittenger (April 1999). "Multilineage potential of adult human mesenchymal stem cells". Science 284 (5411): 143–147. doi:10.1126/science.284.5411.143. PMID 10102814.
- Porcellini A (2009). "Regenerative medicine: a review". Revista Brasileira de Hematologia e Hemoterapia 31 (Suppl. 2). doi:10.1590/S1516-84842009000800017.
- Valero MC, Huntsman HD, Liu J, Zou K, Boppart MD (2012). "Eccentric exercise facilitates mesenchymal stem cell appearance in skeletal muscle". PLoS ONE 7 (1): e29760. doi:10.1371/journal.pone.0029760. PMC 3256189. PMID 22253772.
- Wang S, et al. (2012). "Clinical applications of mesenchymal stem cells". JOURNAL OF HEMATOLOGY & ONCOLOGY 5 (19). doi:10.1186/1756-8722-5-19.
- Branch MJ, Hashmani K, Dhillon P, Jones DR, Dua HS, Hopkinson A (2012). "Mesenchymal stem cells in the human corneal limbal stroma". Invest. Ophthalmol. Vis. Sci. 53 (9): 5109–16. doi:10.1167/iovs.11-8673. PMID 22736610.
- "What is Cord Tissue?". CordAdvantage.com.
- Chong PP, Selvaratnam L, Abbas AA, Kamarul T (2012). "Human peripheral blood derived mesenchymal stem cells demonstrate similar characteristics and chondrogenic differentiation potential to bone marrow derived mesenchymal stem cells". J. Orthop. Res. 30 (4): 634–42. doi:10.1002/jor.21556. PMID 21922534.
- Dylan Bushell-Embling (2015-02-19). "Cynata achieves world-first MSC breakthrough". LifeScientist Australia.
- Hu K et.al (2011). "Efficient generation of transgene-free induced pluripotent stem cells from normal and neoplastic bone marrow and cord blood mononuclear cells.". Blood 117 (14): e109–119. doi:10.1182/blood-2010-07-298331. PMID 21296996.
- Netter, Frank H. (1987). Musculoskeletal system: anatomy, physiology, and metabolic disorders. Summit, New Jersey: Ciba-Geigy Corporation. p. 134. ISBN 0-914168-88-6.
- Brighton CT, Hunt RM (1991). "Early histological and ultrastructural changes in medullary fracture callus". The Journal of Bone and Joint Surgery 73 (6): 832–47. PMID 2071617.
- Hematti P (2012). "Mesenchymal stromal cells and fibroblasts: a case of mistaken identity?". Cytotherapy 14 (5): 516–21. doi:10.3109/14653249.2012.677822. PMID 22458957.
- Dominici M; Le Blanc K; Mueller I; Slaper-Cortenbach I; Marini F; Krause D; Deans R; Keating A; Prockop Dj; Horwitz E (1 January 2006). "Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement". Cytotherapy 8 (4): 315–317. doi:10.1080/14653240600855905. PMID 16923606.
- Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM (2002). "Pluripotency of mesenchymal stem cells derived from adult marrow". Nature 418 (6893): 41–49. doi:10.1038/nature00870. PMID 12077603.
- Franco Lambert AP, Fraga Zandonai A, Bonatto D, Cantarelli Machado D, Pêgas Henriques JA (2009). "Differentiation of human adipose-derived adult stem cells into neuronal tissue: Does it work?". Differentiation 77 (3): 221–8. doi:10.1016/j.diff.2008.10.016. PMID 19272520.
- Engler AJ, Sen S, Sweeney HL, Discher DE (2006). "Matrix Elasticity Directs Stem Cell Lineage Specification". Cell 126 (4): 677–89. doi:10.1016/j.cell.2006.06.044. PMID 16923388.
- Ryan JM, Barry FP, Murphy JM, Mahon BP (2005). "Mesenchymal stem cells avoid allogeneic rejection". Journal of Inflammation 2: 8. doi:10.1186/1476-9255-2-8. PMC 1215510. PMID 16045800.
- Ryan JM, Barry F, Murphy JM, Mahon BP (2007). "Interferon-γ does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells". Clinical & Experimental Immunology 149 (2): 353–63. doi:10.1111/j.1365-2249.2007.03422.x. PMC 1941956. PMID 17521318.
- Phinney DG, Prockop DJ (2007). "Concise Review: Mesenchymal Stem/Multipotent Stromal Cells: The State of Transdifferentiation and Modes of Tissue Repair-Current Views". Stem Cells 25 (11): 2896–902. doi:10.1634/stemcells.2007-0637. PMID 17901396.
- Wan C, He Q, McCaigue M, Marsh D, Li G (2006). "Nonadherent cell population of human marrow culture is a complementary source of mesenchymal stem cells (MSCs)". Journal of Orthopaedic Research 24 (1): 21–8. doi:10.1002/jor.20023. PMID 16419965.
- Gronthos S, Graves SE, Ohta S, Simmons PJ (1994). "The STRO-1+ fraction of adult human bone marrow contains the osteogenic precursors". Blood 84 (12): 4164–73. PMID 7994030.
- Oyajobi BO, Lomri A, Hott M, Marie PJ (1999). "Isolation and Characterization of Human Clonogenic Osteoblast Progenitors Immunoselected from Fetal Bone Marrow Stroma Using STRO-1 Monoclonal Antibody". Journal of Bone and Mineral Research 14 (3): 351–61. doi:10.1359/jbmr.19188.8.131.521. PMID 10027900.
- Tondreau T, Lagneaux L, Dejeneffe M, Delforge A, Massy M, Mortier C, Bron D (1 January 2004). "Isolation of BM mesenchymal stem cells by plastic adhesion or negative selection: phenotype, proliferation kinetics and differentiation potential". Cytotherapy 6 (4): 372–379. doi:10.1080/14653240410004943. PMID 16146890.
- Iudicone P, Fioravanti D, Bonanno G, Miceli M, Lavorino C, Totta P, Frati L, Nuti M, Pierelli L (Jan 2014). "Pathogen-free, plasma-poor platelet lysate and expansion of human mesenchymal stem cells". J Transl Med. 12: 28. doi:10.1186/1479-5876-12-28. PMC 3918216. PMID 24467837.
- Torsvik A, Bjerkvig R (2013). "Mesenchymal stem cell signaling in cancer progression". Cancer Treat Rev. 2 39 (2): 180–8. doi:10.1016/j.ctrv.2012.03.005. PMID 22494966.
- Heirani-Tabasi A, Hassanzadeh M, Hemmati-Sadeghi S, Shahriyari M, Raeesolmohaddeseen M (2015). "Mesenchymal Stem Cells; Defining the Future of Regenerative Medicine". Journal of Genes and Cells 1 (2): 34–9. doi:10.15562/gnc.15.
- Anderson, Johnathon D.; Johansson, Henrik J.; Graham, Calvin S.; Vesterlund, Mattias; Pham, Missy T.; Bramlett, Charles S.; Montgomery, Elizabeth N.; Mellema, Matt S.; Bardini, Renee L. (2016-03-01). "Comprehensive Proteomic Analysis of Mesenchymal Stem Cell Exosomes Reveals Modulation of Angiogenesis via Nuclear Factor-KappaB Signaling". STEM CELLS 34 (3): 601–613. doi:10.1002/stem.2298. ISSN 1549-4918.
- Manieri NA, Stappenbeck TS (2011). "Mesenchymal stem cell therapy of intestinal disease: are their effects systemic or localized?". Current Opinion in Gastroenterology 27 (2): 119–24. doi:10.1097/MOG.0b013e3283423f20. PMID 21150589.
- Fischer UM, Harting MT, Jimenez F, Monzon-Posadas WO, Xue H, Savitz SI, Laine GA, Cox CS (2009). "Pulmonary Passage is a Major Obstacle for Intravenous Stem Cell Delivery: The Pulmonary First-Pass Effect". Stem Cells and Development 18 (5): 683–92. doi:10.1089/scd.2008.0253. PMC 3190292. PMID 19099374.
- Wakitani S, Nawata M, Tensho K, Okabe T, Machida H, Ohgushi H (2007). "Repair of articular cartilage defects in the patello-femoral joint with autologous bone marrow mesenchymal cell transplantation: three case reports involving nine defects in five knees". Journal of Tissue Engineering and Regenerative Medicine 1 (1): 74–9. doi:10.1002/term.8. PMID 18038395.
- Sharma RR, Pollock K, Hubel A, McKenna D (2014). "Mesenchymal stem or stromal cells: a review of clinical applications and manufacturing practices.". Transfusion 54 (5): 1418–37. doi:10.1111/trf.12421. PMID 24898458.
- Figueroa FE, Carrión F, Villanueva S, Khoury M (2012). "Mesenchymal stem cell treatment for autoimmune diseases: a critical review.". Biol Res. 45 (3): 269–77. doi:10.4067/S0716-97602012000300008. PMID 23283436.
- François M, Copland IB, Yuan S, Romieu-Mourez R, Waller EK, Galipeau J (2012). "Cryopreserved mesenchymal stromal cells display impaired immunosuppressive properties as a result of heat-shock response and impaired interferon-γ licensing". Cytotherapy 14 (2): 147–52. doi:10.3109/14653249.2011.623691. PMC 3279133. PMID 22029655.
- Sell, Stewart (Stem cell handbook). Humana Press. p. 143. Check date values in:
|date=(help); Missing or empty
- Becker AJ, McCULLOCH EA, Till JE (1963). "Cytological Demonstration of the Clonal Nature of Spleen Colonies Derived from Transplanted Mouse Marrow Cells". Nature 197 (4866): 452–4. doi:10.1038/197452a0. PMID 13970094.
- Siminovitch L, Mcculloch EA, Till JE (1963). "The distribution of colony-forming cells among spleen colonies". Journal of Cellular and Comparative Physiology 62 (3): 327–36. doi:10.1002/jcp.1030620313. PMID 14086156.
- Friedenstein AJ, Deriglasova UF, Kulagina NN, Panasuk AF, Rudakowa SF, Luriá EA, Ruadkow IA (1974). "Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method". Experimental hematology 2 (2): 83–92. PMID 4455512.
- Friedenstein AJ, Gorskaja JF, Kulagina NN (1976). "Fibroblast precursors in normal and irradiated mouse hematopoietic organs". Experimental hematology 4 (5): 267–74. PMID 976387.
- Mohammad Mousaei Ghasroldasht, Muhammad Irfan-Maqsood, Maryam M. Matin, Hamid Reza Bidkhori, Hojjat Naderi-Meshkin, Ali Moradi and Ahmad Reza Bahrami (2014). "Mesenchymal stem cell based therapy for osteo-diseases". Cell Biology International 9999 (11): 1–5. doi:10.1002/cbin.10293.
- Mesenchymal stem cells fact sheet, published June 2012, scientist-reviewed and not too technical
- Mesenchymal Stem Cell Research at Johns Hopkins University
- Murphy MB, Moncivais K, Caplan AI (2013). "Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine". Experimental & Molecular Medicine 45 (11): e54. doi:10.1038/emm.2013.94. PMC 3849579. PMID 24232253.