[cite journal | author = Szilvassy SJ. | title = The biology of hematopoietic stem cells. | journal = Arch Med Res. | volume = 34 | issue = 6 | pages = 446-60 | year = 2003 | pmid = 14734085 | doi = | url = | issn =] MSCs from embryonic sources have shown promise scientifically while creating significant controversy. As a result, many researchers have focused on adult stem cells [http://www.spinalinjuryfoundation.org/MSC/Stem%20Cell%20Success%20Case%20studies.htm] , or stem cells isolated from adult humans that can be transplanted into damaged tissue.]Because of their multi-potent capabilities, mesenchymal stem cell (MSC) lineages have been used successfully in animal models to regenerate articular cartilage and in human models to regenerate bone. [cite journal | author = Buckwalter JA, Mankin HJ. | title = Articular cartilage: degeneration and osteoarthritis, repair, regeneration, and transplantation. | journal = Instr Course Lect. | volume = 47 | pages = 487-504 | year = 1998 | pmid = 9571450 | doi = | url = | issn =] [cite journal | author = Johnstone B, Yoo JU. | title = Autologous mesenchymal progenitor cells in articular cartilage repair. | journal = Clin Orthop Relat Res. | volume = 367 Suppl | pages = S156-62 | year = 1999 | pmid = 10546644 | doi = | url = | issn =] [cite journal | author = Luyten FP. | title = Mesenchymal stem cells in osteoarthritis. | journal = Curr Opin Rheumatol. | volume = 16 | issue = 5 | pages = 599-603 | year = 2004 | pmid = 15314501 | doi = | url = | issn =] Recent research demonstrates that articular cartilage may be able to be repaired via percutaneous introduction of mesenchymal stem cells (MSC’s) [cite journal | author = Walsh CJ, Goodman D, Caplan AI, Goldberg VM. | title = Meniscus regeneration in a rabbit partial meniscectomy model. | journal = Tissue Eng. | volume = 5 | issue = 4 | pages = 327-37 | year = 1999 | pmid = 10477855 | doi = | url = | issn=] .
Current Research
Research into MSC’s has exploded in recent years. As an example, a PubMed search for the year 1999 reveals about 90 papers published under the MESH heading of “Mesenchymal Stem Cells”, the same search ran for the year 2007 reveals more than 4,000 entries.The most commonly used source of MSC’s is bone marrow aspirate. Most of the adult bone marrow consists of blood cells in various stages of differentiation. [cite journal | author = Verfaillie C, Blakolmer K, McGlave P. | title = Purified primitive human hematopoietic progenitor cells with long-term in vitro repopulating capacity adhere selectively to irradiated bone marrow stroma. | journal = J Exp Med. | volume = 172 | issue = 2 | pages = 509-2 | year = 1990 | pmid = 2373991 | doi = | url = | issn =] These marrow components can be divided into plasma, red blood cells, platelets, and nucleated cells. The adult stem cell fraction is present in the nucleated cells of the marrow. Most of these cells are CD34+ heme progenitors (destined to differentiate into blood components), while very few are actually MSC’s capable of differentiating into bone, cartilage, or muscle. As a result, that leaves the very small number of MSC’s in the marrow as cells capable of differentiating into tissues of interest to joint preservation [http://jointpreservation.wordpress.com/2008/08/21/what-is-joint-preservation/] . Of note, this may be one of the reasons that commercially available centrifuge systems that concentrate marrow nucleated cells have not shown as much promise in animal research for cartilage repair as have approaches where MSC’s are expanded in culture to greater numbers.
Mesenchymal Stem Cell Applications
Marrow nucleated cells are used every day in regenerative orthopedics. The knee microfracture technique popularized by Steadman [http://www.steadman-hawkins.com/physicianSteadman.asp] relies on the release of these cells into a cartilage lesion to initiate fibrocartilage repair in osteochondral defects. [cite journal | author = Steadman JR, Ramappa AJ, Maxwell RB, Briggs KK. | title = An arthroscopic treatment regimen for osteoarthritis of the knee. | journal = Arthroscopy. | volume = 23 | issue = 9 | pages = 948-55 | year = 2007 | pmid = 17868833 | doi = | url = | issn =] In addition, this cell population has also been shown to assist in the repair of non-union fractures. [cite journal | authors = Bruder SP, Fink DJ, Caplan AI. | title = Mesenchymal stem cells in bone development, bone repair, and skeletal regeneration therapy. | journal = J Cell Biochem. | volume = 56 | issue = 3 | pages = 283-94 | year = 1994 | pmid = 7876320 | doi= | url= | issn =] For this application, bed side centrifugation is commonly used. Again, these techniques produce a very dilute MSC population, usually a yield of 1 in 10,000-1,000,000 of the nucleated cells. [cite journal | author = D'Ippolito G, Schiller PC, Ricordi C, Roos BA, Howard GA. | title = Age-related osteogenic potential of mesenchymal stromal stem cells from human vertebral bone marrow. | journal = J Bone Miner Res. | volume = 14 | issue = 7 | pages = 1115-22 | year = 1999 | pmid = 10404011 | doi = | url = | issn =] Despite this low number of MSC’s, isolated bone marrow nucleated cells implanted into degenerated human peripheral joints have shown some promise for joint repair. [cite journal | author = Centeno CJ, Kisiday J, Freeman M, Schultz JR. | title = Partial regeneration of the human hip via autologous bone marrow nucleated cell transfer: A case study. | journal = Pain Physician. | volume = 9 | issue = 3 | pages = 253-6 | year = 2006 | pmid = 16886034 | doi = | url = | issn=] As the number of MSC’s that can be isolated from bone marrow is fairly limited, most research in cartilage regeneration has focused on the use of culture expanded cells. [cite journal | author = Gao J, Caplan AI. | title = Mesenchymal stem cells and tissue engineering for orthopaedic surgery. | journal = 88 | issue = 3 | pages = 305-16 | year = 2003 | pmid = 15146948 | doi = | url = | issn =] [cite journal | author = Xiang Y, Zheng Q, Jia BB, Huang GP, Xu YL, Wang JF, Pan ZJ. | title = Ex vivo expansion and pluripotential differentiation of cryopreserved human bone marrow mesenchymal stem cells. | journal = J Zhejiang Univ Sci B. | volume = 8 | issue = 2 | pages = 136-36 | year = 2007 | pmid = 17266190 | doi = | url = | issn =] . This method can expand cell numbers by 100-10,000 fold over several weeks. Once these MSCs are ready for reimplanation, they are usually transferred with growth factors to allow for continued cell growth and engraftment to the damaged tissue. At some point, a signal is introduced (either in culture or after transplant to the damaged tissue) for the cells to differentiate into the end tissue (in this discussion, cartilage).
Recent Developments
Until recently, the use of cultured mesenchymal stem cells to regenerate cartilage has been primarily in research with animal models. There are now, however, two published case reports of this technique being used to successfully regenerate articular and meniscus cartilage in human knees [http://www.painphysicianjournal.com/2008/may/2008;11;343-353.pdf] [http://www.amjcaserep.com/fulltxt.php?ICID=855038] . [cite journal | author = Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M, Karli D. | title = Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells. | journal = Pain Physician. | volume = 11 | issue = 3 | pages = 343-53 | year = 2008 | pmid = 18523506 | doi = | url = | issn = ] [cite journal | author = Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M. | title = Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells, platelet lysate and dexamethasone. | journal = Am J Case Rep | volume = 9 | pages = CR246-251 | year = 2008 | pmid = | url = | doi = | issn =] Applications of this technology to other joints and tissues: such as hips, shoulders, thumbs, ankles, ligaments, and tendons are steps in a move away from traditional surgical repair and replacement of worn out joints in favor of cartilage regeneration and tissue repair.
References
