View source for Biology:Stem cell transplantation for articular cartilage repair

{{Short description|Medical procedure}}
Mesenchymal stem cells (MSCs) are multipotent cells found in multiple human adult tissues, including bone marrow, synovial tissues, and adipose tissues.  Since they are derived from the [[Biology:Mesoderm|mesoderm]], they have been shown to differentiate into bone, cartilage, muscle, and adipose tissue.<ref name=Szilvassy>{{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 = 10.1016/j.arcmed.2003.06.004 }}</ref><ref>
{{cite journal |vauthors=Mahla RS| title = Stem cells application in regenerative medicine and disease therapeutics | journal = International Journal of Cell Biology  | volume = 2016 | issue = 7 | pages = 1–24 | year = 2016 | pmid = 27516776 | pmc = 4969512 | doi = 10.1155/2016/6940283 | doi-access = free }}</ref> MSCs from embryonic sources have shown promise scientifically while creating significant controversy.  As a result, many researchers have focused on adult stem cells,<ref>[http://www.spinalinjuryfoundation.org/MSC/Stem%20Cell%20Success%20Case%20studies.htm Spinal Injury Foundation]</ref> 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.<ref>{{cite journal |vauthors=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 }}</ref><ref>{{cite journal |vauthors=Johnstone B, Yoo JU | title = Autologous mesenchymal progenitor cells in articular cartilage repair. | journal = Clin Orthop Relat Res | volume = 367 |issue=Suppl | pages = S156–62 | year = 1999 | pmid = 10546644 | doi = 10.1097/00003086-199910001-00017 }}</ref><ref>{{cite journal | author = Luyten FP. | title = Mesenchymal stem cells in osteoarthritis | journal = Current Opinion in Rheumatology  | volume = 16 | issue = 5 | pages = 599–603 | year = 2004 | pmid = 15314501 | doi = 10.1097/01.bor.0000130284.64686.63 | s2cid = 20638965 }}</ref>  Recent research demonstrates that articular cartilage may be able to be repaired via the percutaneous introduction of mesenchymal stem cells (MSC's).<ref>{{cite journal |vauthors=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 = 10.1089/ten.1999.5.327 }}</ref>

Stem cells, as a concept, originated as a theory in the 19th century to potentially allow certain tissues to self-renew. There are five types of stem cells, and MSC's are multi-potent, meaning they are cells that have the ability to develop into more than one type of specialized cell. Mesenchymal stem cells were originally discovered and studied as fibroblast-colony-forming cells in guinea-pig bone marrow and spleen cells by Friedenstein in the 1970s.<ref>{{Cite journal|last1=Friedenstein|first1=A. J.|last2=Chailakhjan|first2=R. K.|last3=Lalykina|first3=K. S.|date=October 1970|title=The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells|url=https://pubmed.ncbi.nlm.nih.gov/5523063/|journal=Cell and Tissue Kinetics|volume=3|issue=4|pages=393–403|doi=10.1111/j.1365-2184.1970.tb00347.x|issn=0008-8730|pmid=5523063|s2cid=45546484 }}</ref> This study proved that the colony-forming units of bone marrow-derived stem cells were able to form cartilage once they were transplanted into a diffusion chamber.<ref>{{Cite book|last1=Owen|first1=M.|last2=Friedenstein|first2=A. J.|title=Ciba Foundation Symposium 136 ‐ Cell and Molecular Biology of Vertebrate Hard Tissues |chapter=Stromal Stem Cells: Marrow‐Derived Osteogenic Precursors |date=1988|chapter-url=https://pubmed.ncbi.nlm.nih.gov/3068016/|series=Novartis Foundation Symposia |volume=136|pages=42–60|doi=10.1002/9780470513637.ch4|issn=0300-5208|pmid=3068016|isbn=9780470513637 }}</ref> The results of this study set the stage for future research by indicating the differentiation capacity of MSC's.{{citation needed|date=February 2022}}

==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 "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.<ref>{{cite journal |vauthors=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 = 509–02 | year = 1990 | pmid = 2373991 | doi = 10.1084/jem.172.2.509 | pmc = 2188338 }}</ref>  These marrow components can be divided into [[Biology:Blood plasma|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 a very small number of MSC's in the marrow as cells capable of differentiating into tissues of interest to joint preservation.<ref>{{cite web |url=http://jointpreservation.wordpress.com/2008/08/21/what-is-joint-preservation/ |title=What is joint preservation? |work=Joint Preservation Blog |date=2008-08-21 }}</ref>  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.<ref>{{Cite journal|last1=Goldberg|first1=Andy|last2=Mitchell|first2=Katrina|last3=Soans|first3=Julian|last4=Kim|first4=Louise|last5=Zaidi|first5=Razi|date=2017-03-09|title=The use of mesenchymal stem cells for cartilage repair and regeneration: a systematic review|journal=Journal of Orthopaedic Surgery and Research|volume=12|issue=1|page=39|doi=10.1186/s13018-017-0534-y|issn=1749-799X|pmc=5345159|pmid=28279182 |doi-access=free }}</ref>

==Mesenchymal stem cell applications==

Marrow-nucleated cells are used every day in regenerative orthopedics.  The knee [[Medicine:Microfracture surgery|microfracture surgery]] technique relies on the release of these cells into a cartilage lesion to initiate fibrocartilage repair in osteochondral defects.<ref>{{cite journal |vauthors=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 = 10.1016/j.arthro.2007.03.097 }}</ref>  In addition, this cell population has also been shown to assist in the repair of non-union fractures.<ref>{{cite journal | 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 |vauthors=Bruder SP, Fink DJ, Caplan AI | doi = 10.1002/jcb.240560303 | pmc = 7166813 }}</ref>  For this application, bedside 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.<ref>{{cite journal |vauthors=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 = 10.1359/jbmr.1999.14.7.1115 | doi-access = free }}</ref>  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.<ref>{{cite journal |vauthors=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 = 253–56 | year = 2006 | pmid = 16886034 }}</ref> 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.<ref>{{cite journal |vauthors=Gao J, Caplan AI | title = Mesenchymal stem cells and tissue engineering for orthopaedic surgery. | issue = 3 | pages = 305–16 | year = 2003 | pmid = 15146948 | volume = 88 | journal = La Chirurgia Degli Organi di Movimento }}</ref><ref>{{cite journal |vauthors=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 = 10.1631/jzus.2007.B0136 | pmc = 1791057 }}</ref>  This method can expand cell numbers by 100–10,000 fold over several weeks.  Once these MSCs are ready for re-implantation, 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<ref>{{Cite journal|last1=Biehl|first1=Jesse K.|last2=Russell|first2=Brenda|date=2009|title=Introduction to Stem Cell Therapy|journal=The Journal of Cardiovascular Nursing|volume=24|issue=2|pages=98–105|doi=10.1097/JCN.0b013e318197a6a5|issn=0889-4655|pmc=4104807|pmid=19242274}}</ref>

==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 the above technique being used to successfully regenerate articular and meniscus cartilage in human knees.<ref>{{cite journal | vauthors = 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 | url = http://www.painphysicianjournal.com/2008/may/2008;11;343-353.pdf | access-date = 2008-09-05 | archive-date = 2013-11-26 | archive-url = https://web.archive.org/web/20131126051842/http://www.painphysicianjournal.com/2008/may/2008;11;343-353.pdf | url-status = dead }}</ref><ref>{{cite journal |vauthors=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 = CR246–51 | year = 2008 |url=http://www.amjcaserep.com/fulltxt.php?ICID=855038}}</ref> This technique has yet to be shown effective in a study involving a larger group of patients; however, the same team of researchers has published a large safety study (n = 227) showing fewer complications than would normally be associated with surgical procedures.<ref>{{cite journal |vauthors=Centeno CJ, Schultz JR, Cheever M, Robinson B, Freeman M, Marasco W | title = Safety and Complications Reporting on the Re-implantation of Culture-Expanded Mesenchymal Stem Cells using Autologous Platelet Lysate Technique. | journal = Current Stem Cell Research & Therapy  | pmid = 19951252 | year = 2010 | volume = 5 | issue = 1 | pages = 81–93 | doi = 10.2174/157488810790442796 | s2cid = 20901900 }}</ref>

Another team used a similar technique for cell extraction and ex vivo expansion, but cells were embedded within a collagen gel before being surgically re-implanted.  They reported a case study in which a full-thickness defect in the articular cartilage of a human knee was successfully repaired.<ref>{{cite journal |vauthors=Kuroda R, Ishida K, Matsumoto T, Akisue T, Fujioka H, Mizuno K, Ohgushi H, Wakitani S, Kurosaka M | title = Treatment of a full-thickness articular cartilage defect in the femoral condyle of an athlete with autologous bone-marrow stromal cells | journal = Osteoarthritis and Cartilage | year = 2007 | volume = 15 | issue = 2 | pages = 226–31 | doi = 10.1016/j.joca.2006.08.008 | pmid = 17002893| doi-access = free }}</ref>

While the use of cultured mesenchymal stem cells has shown promising results, a more recent study using uncultured MSC's has resulted in full-thickness, histologically confirmed hyaline cartilage regrowth.  Researchers evaluated the quality of the repaired knee cartilage after arthroscopic microdrilling ([[Medicine:Microfracture surgery|also microfracture]]) surgery followed by post-operative injections of autologous peripheral blood progenitor cells (PBPC) in combination with [[Chemistry:Sodium hyaluronate|hyaluronic acid]] (HA).<ref>{{cite journal|last=Saw|first=KY|author2=Anz A|author3=Merican S|author4=Tay YG|author5=Ragavanaidu K|author6=Jee CS|author7=McGuire DA|date=April 2011|title=Articular cartilage regeneration with autologous peripheral blood progenitor cells and hyaluronic Acid after arthroscopic subchondral drilling: a report of 5 cases with histology|journal=Arthroscopy|volume=27|issue=4|pages=493–506|doi=10.1016/j.arthro.2010.11.054|pmid=21334844}}</ref>

==References==
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{{DEFAULTSORT:Stem Cell Transplantation For Articular Cartilage Repair}}
[[Category:Stem cells]]

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