Cell Therapy For Articular Cartilage

Introduction

Articular cartilage is the highly specialized connective tissue of diartrodial joints. It’s principal function is to provide a smooth, lubricated surface for articulation and to facilitate the transmission of loads with a low frictional coefficient. Articular cartilage is hyaline cartilage and is 2- 4 mm thick. Unlike most tissues articular cartilage doesn’t have blood vessels, nerve or lymphatics. It is composed of a dense extracellular matrix ( ECM) with a sparse distribution of highly specialized cells called chondrocytes The ECM is principally composed of water, collagen and proteoglycans with other noncollageneous proteins present in lesser amount.

Although the cartilage contains only a single type of cell (chondrocytes) the cells in different layers have distinct morphologies and functionalities . This tissue is usually divided into 4 zones- i) the superficial zone in contact with synovial fluid, containing chondro- progenitors , ii) the middle or transitional zone beneath the superficial zone, containing round chondrocytes, iii) the deep or radial zone and iv) the calcified layer in direct contact with underlying subchondral zone.

Degenerative lessons of Articular cartilage as a consequence of destructive joint disease, such as osteoarthritis (OA) , can lead to disability, pain during movement of joints, and gradual deformation of the bone articulation. OA is the most common musculoskeletal disorder, affecting 10 – 12% of the global population. Clinically available cartilage repair can be divided into two sub – categories: surgical approaches and those based on regenerative medicine ( e.g.: implantation of expanded autologous chondrocytes) . The wide variety of approaches to restoration under development involve cell expansion and differentiation into mature chondrocytes with different combinations of scaffolding, stem cells, and native cartilage environment.

Pathophysiology of OA

Osteoarthritis is an adiopathic disease characterized by degeneration of articular cartilage. A breakdown of the cartilage matrix leads to the development of fibrillation of fissures, the appearance of gross ulceration, and the disappearance of the full thickness surface of the joint. This is accompanied by bone changes with osteophyte formation and thickening of the subchondral plate. Moreover, at the clinical stage of the disease, changes caused by OA involve not only the cartilage but also the synovial membrane, where an inflammatory reaction is often observed.

Current treatment modalities

Microfracture and similar techniques ( i.e., abrasion and drilling) involve disrupting the subchondral bone integrity to create channels between the defects in the cartilage and underlying bone marrow. It is generally accepted that the recruitment of multi- potent marrow stromal cells to the defects through these channels leads to subsequent formation of tissue resembling articular cartilage. However, this approach is only effective for small defects. Mosaicplasty/ osteochondral Grafting involves the replacement of the lost cartilage with tissue grafts, i.e., an osteochondral allograft or autologous transplant harvested from the patient’s own cartilage. In the later case, small cylindrical plugs taken from non- weight- bearing areas are fitted into the defects.

Autologous chondrocyte implantation (ACI) is a cell- based technique to treat the full – thickness chondral defects in the knee. It was developed by Brittberg and colleagues in 1994. Here the cartilage tissue is first harvested from the patient by artroscopy from a non-weight bearing area .Then the chondrocytes are isolated and culture in the laboratory to form a monolayer culture to get the desired population of chondrocytes. Thereafter, they are transplanted into the cartilage defect and held in place by sewing a periosteum patch over it so as to localise the chondrocytes within the defect site. Matrix- induced autologous chondrocyte implimentation (MACI) involves transplantation of a special three- dimensional scaffold comprised of autologous chondrocytes into cartilage defects.

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Mesenchymal stem cells

Mesenchymal stem cells (MSCs) from different sources, such as the bone marrow, adipose tissue, synovial membrane, cord blood, periosteum, and muscle , are employed to treat defects in articular cartilage. The ability to differentiate into chondrocytes varies between MSCs obtained from different sources, with synovial MSCs demonstrating the greatest potential to differentiate into articular chondrocytes. However, the transplantation of MSCs often gives rise to a mixture of hypertonic, cartilaginous, and fibrous tissues, which is not particularly sustainable, and ,in the long run, leads to a loss of repair tissue. Thus , a further development of culture/ differentiation protocols is required before MSCs can be utilized successfully for joint repair.

Embryonic stem cells

Embryonic stem cells (ESCs) posses unlimited potential for proliferation and differentiation into virtually any type of somatic cell. The various procedures for the conversion of ESCs into chondrocytes include co -culture with primary articular chondrocytes and the production of cells resembling mesenchymal stem cells from ESCs, followed by their differentiation into chondrocytes employing a variety of growth factors.

The most successful differentiation of ESCs into chondrocytes involves differentiation- mimicking embryonic development, i.e, the induction of primitive streak cells with BMP4 and bFGF, followed by the generation of paraxial mesoderm via the inhibition of BMP signaling in the presence of bFGF, the generation of chondrocyte progenitors in high- density culture in the presence of TGF-beta3, and the production of articular chondrocytes with time. The drawbacks associated with the utilization of ESCs for cartilage regeneration include ethical concerns about the destruction of a human embryo, immune rejection by the host, poor survival of human ESCs following disintegration of the cell mass, and the risk for teratoma formation.

Induced pluripotent stem cells

Induced pluripotent stem cells (iPSCs) represent a relatively new source of stem cells with the capacity for self- renewal and pluripotent similar to that of ESCs, but without the same ethical and immunogenic concerns. The iPSCs are obtained by reprogramming somatic cells in vitro to enter an embryonic- like pluripotent state through the introduction and forced expression of the four transcription factors (TFs) – Oct4, Sox2, cMyc, Klf4, referred to collectively as Yamanaka factors. Although these cells can be generated from many different types of somatic cells, skin fibroblasts are the major source because of the ease with which they can be obtained. Among the various approaches for inducing the chondrogenic differentiation of human iPSCs, the most promising mimic natural development, with monolayer cultures of iPSCs first differentiating into the mesoendoderm, followed by further differentiation into chondrogenic cultures. The steps in the process vary slightly between laboratories; however, in general, they include the modulation of BMP, FGF, and Wingless- type MMTV integration site signaling pathways, as well as alteration in culture condition, such as the monolayer cell density, 2D versus 3D culture, etc.

Chondrogenic Stem/progenitor cells from the superficial zone

A promising cell source, cartilage stem/progenitor cells (CSPCs), has attracted recent attention. Because their origin and identity are still unclear, the application potential of CSPCs is under active investigation. Here we have captured the emergence of a group of stem/progenitor cells derived from adult human chondrocytes, highlighted by dynamic changes in expression of the mature chondrocyte marker, COL2, and mesenchymal stromal/stem cell (MSC) marker, CD146. These cells are termed chondrocyte-derived progenitor cells (CDPCs). The stem cell-like potency and differentiation status of CDPCs were determined by physical and biochemical cues during culture. A low-density, low- glucose 2-dimensional culture condition (2DLL) was critical for the emergence and proliferation enhancement of CDPCs. CDPCs showed similar phenotype as bone marrow mesenchymal stromal/stem cells but exhibited greater chondrogenic potential.

Conclusion

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. This technique has yet to be shown effective in a study involving a larger group of patients, however the same team of researchers have published a large safety study (n=227) showing fewer complications than would normally be associated with surgical procedures. 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.

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 repair 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).

References

1. Ekaterina V.Medvedeva, Ekaterina A. Grebenik, Svetlana N. Gornosteva. Repair of damaged articular cartilage: current approaches and future directions.
2. Alice J. Sophia Fox, Asheesh Bedi, and Scott.A.Rodeo. The basic science of articular cartilage.
3. Shari M. Ling, Joan M. Bathon. Osteoarthritis : pathophysiology
4. Yoojun Nam, Yeri Alice Rim, Jennifer Lee and Ji Hyeon Jn. Current therapeutic strategies for stem cell based cartilage regeneration.
5. Mobasheri A. et Al. Mesenchymal stem cells in connective tissue engineering and regenerative medicine: applications in cartilage repair and osteoarthritis therapy.
6. Anthony R. Martin, Jay M. Patel, Hannah M. Zlotnick, James L. Carey and Robert L. Mauck. Emerging therapies for cartilage regeneration in currently excluded ‘red knee’ populations.