Stem cell transplantation for articular cartilage repair

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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 mesoderm, they have been shown to differentiate into bone, cartilage, muscle, and adipose tissue. [1] [2] MSCs from embryonic sources have shown promise scientifically while creating significant controversy. As a result, many researchers have focused on adult stem cells, [3] or stem cells isolated from adult humans that can be transplanted into damaged tissue.

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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. [4] [5] [6] Recent research demonstrates that articular cartilage may be able to be repaired via the percutaneous introduction of mesenchymal stem cells (MSC's). [7]

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. [8] 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. [9] The results of this study set the stage for future research by indicating the differentiation capacity of MSC's.[ citation needed ]

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. [10] 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 a very small number of MSC's in the marrow as cells capable of differentiating into tissues of interest to joint preservation. [11] 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. [12]

Mesenchymal stem cell applications

Marrow-nucleated cells are used every day in regenerative orthopedics. The knee microfracture surgery technique relies on the release of these cells into a cartilage lesion to initiate fibrocartilage repair in osteochondral defects. [13] In addition, this cell population has also been shown to assist in the repair of non-union fractures. [14] 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. [15] 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. [16] 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. [17] [18] 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 [19]

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. [20] [21] 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. [22]

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. [23]

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 (also microfracture) surgery followed by post-operative injections of autologous peripheral blood progenitor cells (PBPC) in combination with hyaluronic acid (HA). [24]

Related Research Articles

<span class="mw-page-title-main">Stem cell</span> Undifferentiated biological cells that can differentiate into specialized cells

In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of cell in a cell lineage. They are found in both embryonic and adult organisms, but they have slightly different properties in each. They are usually distinguished from progenitor cells, which cannot divide indefinitely, and precursor or blast cells, which are usually committed to differentiating into one cell type.

<span class="mw-page-title-main">Cell therapy</span> Therapy in which cellular material is injected into a patient

Cell therapy is a therapy in which viable cells are injected, grafted or implanted into a patient in order to effectuate a medicinal effect, for example, by transplanting T-cells capable of fighting cancer cells via cell-mediated immunity in the course of immunotherapy, or grafting stem cells to regenerate diseased tissues.

<span class="mw-page-title-main">Adult stem cell</span> Multipotent stem cell in the adult body

Adult stem cells are undifferentiated cells, found throughout the body after development, that multiply by cell division to replenish dying cells and regenerate damaged tissues. Also known as somatic stem cells, they can be found in juvenile, adult animals, and humans, unlike embryonic stem cells.

<span class="mw-page-title-main">Chondroblast</span> Mesenchymal progenitor cell that forms a chondrocyte

Chondroblasts, or perichondrial cells, is the name given to mesenchymal progenitor cells in situ which, from endochondral ossification, will form chondrocytes in the growing cartilage matrix. Another name for them is subchondral cortico-spongious progenitors. They have euchromatic nuclei and stain by basic dyes.

Stem-cell therapy is the use of stem cells to treat or prevent a disease or condition. As of 2016, the only established therapy using stem cells is hematopoietic stem cell transplantation. This usually takes the form of a bone-marrow transplantation, but the cells can also be derived from umbilical cord blood. Research is underway to develop various sources for stem cells as well as to apply stem-cell treatments for neurodegenerative diseases and conditions such as diabetes and heart disease.

Articular cartilage, most notably that which is found in the knee joint, is generally characterized by very low friction, high wear resistance, and poor regenerative qualities. It is responsible for much of the compressive resistance and load bearing qualities of the knee joint and, without it, walking is painful to impossible. Osteoarthritis is a common condition of cartilage failure that can lead to limited range of motion, bone damage and invariably, pain. Due to a combination of acute stress and chronic fatigue, osteoarthritis directly manifests itself in a wearing away of the articular surface and, in extreme cases, bone can be exposed in the joint. Some additional examples of cartilage failure mechanisms include cellular matrix linkage rupture, chondrocyte protein synthesis inhibition, and chondrocyte apoptosis. There are several different repair options available for cartilage damage or failure.

<span class="mw-page-title-main">Microfracture surgery</span> Cartilage repair technique

Microfracture surgery is an articular cartilage repair surgical technique that works by creating tiny fractures in the underlying bone. This causes new cartilage to develop from a so-called super-clot.

<span class="mw-page-title-main">Sp7 transcription factor</span> Protein-coding gene in the species Homo sapiens

Transcription factor Sp7, also called osterix (Osx), is a protein that in humans is encoded by the SP7 gene. It is a member of the Sp family of zinc-finger transcription factors It is highly conserved among bone-forming vertebrate species It plays a major role, along with Runx2 and Dlx5 in driving the differentiation of mesenchymal precursor cells into osteoblasts and eventually osteocytes. Sp7 also plays a regulatory role by inhibiting chondrocyte differentiation maintaining the balance between differentiation of mesenchymal precursor cells into ossified bone or cartilage. Mutations of this gene have been associated with multiple dysfunctional bone phenotypes in vertebrates. During development, a mouse embryo model with Sp7 expression knocked out had no formation of bone tissue. Through the use of GWAS studies, the Sp7 locus in humans has been strongly associated with bone mass density. In addition there is significant genetic evidence for its role in diseases such as Osteogenesis imperfecta (OI).

Articular cartilage repair treatment involves the repair of the surface of the articular joint's hyaline cartilage, though these solutions do not perfectly restore the articular cartilage. These treatments have been shown to have positive results for patients who have articular cartilage damage. They can provide some measure of pain relief, while slowing down the accumulation of damage, or delaying the need for joint replacement surgery.

Autologous chondrocyte implantation is a biomedical treatment that repairs damages in articular cartilage. ACI provides pain relief while at the same time slowing down the progression or considerably delaying partial or total joint replacement surgery. The goal of ACI is to allow people suffering from articular cartilage damage to return to their old lifestyle; regaining mobility, going back to work and even practicing sports again.

Amniotic stem cells are the mixture of stem cells that can be obtained from the amniotic fluid as well as the amniotic membrane. They can develop into various tissue types including skin, cartilage, cardiac tissue, nerves, muscle, and bone. The cells also have potential medical applications, especially in organ regeneration.

<span class="mw-page-title-main">Osteochondroprogenitor cell</span>

Osteochondroprogenitor cells are progenitor cells that arise from mesenchymal stem cells (MSC) in the bone marrow. They have the ability to differentiate into osteoblasts or chondrocytes depending on the signalling molecules they are exposed to, giving rise to either bone or cartilage respectively. Osteochondroprogenitor cells are important for bone formation and maintenance.

<span class="mw-page-title-main">Mesenchymal stem cell</span> Multipotent, non-hematopoietic adult stem cells present in multiple tissues

Mesenchymal stem cells (MSCs) also known as mesenchymal stromal cells or medicinal signaling cells are multipotent stromal cells that can differentiate into a variety of cell types, including osteoblasts, chondrocytes, myocytes and adipocytes.

Adult mesenchymal stem cells are being used by researchers in the fields of regenerative medicine and tissue engineering to artificially reconstruct human tissue which has been previously damaged. Mesenchymal stem cells are able to differentiate, or mature from a less specialized cell to a more specialized cell type, to replace damaged tissues in various organs.

Cartilage repair techniques are the current focus of large amounts of research. Many different strategies have been proposed as solutions for cartilage defects. Surgical techniques currently being studied include:

Nasal chondrocytes (NC) are present in the hyaline cartilage of the nasal septum and in fact are the only cell type within the tissue. Similar to chondrocytes present in articular cartilage, NC express extracellular matrix proteins such as glycosaminoglycans and collagen.

Artificial cartilage is a synthetic material made of hydrogels or polymers that aims to mimic the functional properties of natural cartilage in the human body. Tissue engineering principles are used in order to create a non-degradable and biocompatible material that can replace cartilage. While creating a useful synthetic cartilage material, certain challenges need to be overcome. First, cartilage is an avascular structure in the body and therefore does not repair itself. This creates issues in regeneration of the tissue. Synthetic cartilage also needs to be stably attached to its underlying surface i.e. the bone. Lastly, in the case of creating synthetic cartilage to be used in joint spaces, high mechanical strength under compression needs to be an intrinsic property of the material.

Craniofacial regeneration refers to the biological process by which the skull and face regrow to heal an injury. This page covers birth defects and injuries related to the craniofacial region, the mechanisms behind the regeneration, the medical application of these processes, and the scientific research conducted on this specific regeneration. This regeneration is not to be confused with tooth regeneration. Craniofacial regrowth is broadly related to the mechanisms of general bone healing.

<span class="mw-page-title-main">Mohamadreza Baghaban Eslaminejad</span>

Mohamadreza Baghaban Eslaminejad is the director of the Adult Stem Cell Lab and histology/embryology Professor at the Royan Institute where he held a multi-departmental professorship in bioengineering, tissue engineering, regenerative medicine, and stem cell therapy. Eslaminejad studies have been cited over 4000 times. He is best known for Hard Tissue Engineering and utilizing Mesenchymal stem cells for treatment of orthopedic diseases.

<span class="mw-page-title-main">Stem cell fat grafting</span>

Stem cellfat grafting is autotransplantation of adipose-derived stem cells (ADSCs) extracted from fat-abundant donor sites to other areas such as the face, breast, and hip to reconstruct the operative areas into desirable shapes. ADSCs are multipotent stem cells found in adipose tissues, displaying similar differentiation potentials to bone marrow-derived mesenchymal stem cells (BM-MSCs).

References

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  2. ↑ Mahla RS (2016). "Stem cells application in regenerative medicine and disease therapeutics". International Journal of Cell Biology. 2016 (7): 1–24. doi: 10.1155/2016/6940283 . PMC   4969512 . PMID   27516776.
  3. ↑ Spinal Injury Foundation
  4. ↑ Buckwalter JA, Mankin HJ (1998). "Articular cartilage: degeneration and osteoarthritis, repair, regeneration, and transplantation". Instr Course Lect. 47: 487–504. PMID   9571450.
  5. ↑ Johnstone B, Yoo JU (1999). "Autologous mesenchymal progenitor cells in articular cartilage repair". Clin Orthop Relat Res. 367 (Suppl): S156–62. doi:10.1097/00003086-199910001-00017. PMID   10546644.
  6. ↑ Luyten FP. (2004). "Mesenchymal stem cells in osteoarthritis". Current Opinion in Rheumatology. 16 (5): 599–603. doi:10.1097/01.bor.0000130284.64686.63. PMID   15314501. S2CID   20638965.
  7. ↑ Walsh CJ, Goodman D, Caplan AI, Goldberg VM (1999). "Meniscus regeneration in a rabbit partial meniscectomy model". Tissue Eng. 5 (4): 327–37. doi:10.1089/ten.1999.5.327. PMID   10477855.
  8. ↑ Friedenstein, A. J.; Chailakhjan, R. K.; Lalykina, K. S. (October 1970). "The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells". Cell and Tissue Kinetics. 3 (4): 393–403. doi:10.1111/j.1365-2184.1970.tb00347.x. ISSN   0008-8730. PMID   5523063. S2CID   45546484.
  9. ↑ Owen, M.; Friedenstein, A. J. (1988). "Stromal Stem Cells: Marrow‐Derived Osteogenic Precursors". Ciba Foundation Symposium 136 ‐ Cell and Molecular Biology of Vertebrate Hard Tissues. Novartis Foundation Symposia. Vol. 136. pp. 42–60. doi:10.1002/9780470513637.ch4. ISBN   9780470513637. ISSN   0300-5208. PMID   3068016.
  10. ↑ Verfaillie C, Blakolmer K, McGlave P (1990). "Purified primitive human hematopoietic progenitor cells with long-term in vitro repopulating capacity adhere selectively to irradiated bone marrow stroma". J Exp Med. 172 (2): 509–02. doi:10.1084/jem.172.2.509. PMC   2188338 . PMID   2373991.
  11. ↑ "What is joint preservation?". Joint Preservation Blog. 2008-08-21.
  12. ↑ Goldberg, Andy; Mitchell, Katrina; Soans, Julian; Kim, Louise; Zaidi, Razi (2017-03-09). "The use of mesenchymal stem cells for cartilage repair and regeneration: a systematic review". Journal of Orthopaedic Surgery and Research. 12 (1): 39. doi: 10.1186/s13018-017-0534-y . ISSN   1749-799X. PMC   5345159 . PMID   28279182.
  13. ↑ Steadman JR, Ramappa AJ, Maxwell RB, Briggs KK (2007). "An arthroscopic treatment regimen for osteoarthritis of the knee". Arthroscopy. 23 (9): 948–55. doi:10.1016/j.arthro.2007.03.097. PMID   17868833.
  14. ↑ Bruder SP, Fink DJ, Caplan AI (1994). "Mesenchymal stem cells in bone development, bone repair, and skeletal regeneration therapy". J Cell Biochem. 56 (3): 283–94. doi:10.1002/jcb.240560303. PMC   7166813 . PMID   7876320.
  15. ↑ D'Ippolito G, Schiller PC, Ricordi C, Roos BA, Howard GA (1999). "Age-related osteogenic potential of mesenchymal stromal stem cells from human vertebral bone marrow". J Bone Miner Res. 14 (7): 1115–22. doi: 10.1359/jbmr.1999.14.7.1115 . PMID   10404011.
  16. ↑ Centeno CJ, Kisiday J, Freeman M, Schultz JR (2006). "Partial regeneration of the human hip via autologous bone marrow nucleated cell transfer: A case study". Pain Physician. 9 (3): 253–56. PMID   16886034.
  17. ↑ Gao J, Caplan AI (2003). "Mesenchymal stem cells and tissue engineering for orthopaedic surgery". La Chirurgia Degli Organi di Movimento. 88 (3): 305–16. PMID   15146948.
  18. ↑ Xiang Y, Zheng Q, Jia BB, Huang GP, Xu YL, Wang JF, Pan ZJ (2007). "Ex vivo expansion and pluripotential differentiation of cryopreserved human bone marrow mesenchymal stem cells". J Zhejiang Univ Sci B. 8 (2): 136–36. doi:10.1631/jzus.2007.B0136. PMC   1791057 . PMID   17266190.
  19. ↑ Biehl, Jesse K.; Russell, Brenda (2009). "Introduction to Stem Cell Therapy". The Journal of Cardiovascular Nursing. 24 (2): 98–105. doi:10.1097/JCN.0b013e318197a6a5. ISSN   0889-4655. PMC   4104807 . PMID   19242274.
  20. ↑ Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M, Karli D (2008). "Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells" (PDF). Pain Physician. 11 (3): 343–53. PMID   18523506. Archived from the original (PDF) on 2013-11-26. Retrieved 2008-09-05.
  21. ↑ Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M (2008). "Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells, platelet lysate and dexamethasone". Am J Case Rep. 9: CR246–51.
  22. ↑ Centeno CJ, Schultz JR, Cheever M, Robinson B, Freeman M, Marasco W (2010). "Safety and Complications Reporting on the Re-implantation of Culture-Expanded Mesenchymal Stem Cells using Autologous Platelet Lysate Technique". Current Stem Cell Research & Therapy. 5 (1): 81–93. doi:10.2174/157488810790442796. PMID   19951252. S2CID   20901900.
  23. ↑ Kuroda R, Ishida K, Matsumoto T, Akisue T, Fujioka H, Mizuno K, Ohgushi H, Wakitani S, Kurosaka M (2007). "Treatment of a full-thickness articular cartilage defect in the femoral condyle of an athlete with autologous bone-marrow stromal cells". Osteoarthritis and Cartilage. 15 (2): 226–31. doi: 10.1016/j.joca.2006.08.008 . PMID   17002893.
  24. ↑ Saw, KY; Anz A; Merican S; Tay YG; Ragavanaidu K; Jee CS; McGuire DA (April 2011). "Articular cartilage regeneration with autologous peripheral blood progenitor cells and hyaluronic Acid after arthroscopic subchondral drilling: a report of 5 cases with histology". Arthroscopy. 27 (4): 493–506. doi:10.1016/j.arthro.2010.11.054. PMID   21334844.
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