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Haddadi K. Degenerative Disc Disease: A Review of Cell Technologies and Stem Cell Therapy. IrJNS. 2016; 1 (4) :6-10
URL: http://irjns.org/article-1-24-en.html
Assistant Professor
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At this time, degenerative disk disease (DDD) and the following chronic back pain characterize an important cause of morbidity and mortality universally (1,2). The purpose of accessible treatment modalities such as pain treatment and operations is to offer symptomatic relief; but they do not reduce the original pathophysiology of DDD. The disease by itself has high social health care expences (3). Magnetic resonance imaging (MRI) is a noninvasive and choice method to evaluate lumbar disc herniation and to exclude the different differential diagnosis in spine and other organs of body (4,5).
Numerous modalities are used for symptomatic handling of this disorder, containing bed rest, massage, stretching, exercises, physical therapy, epidural injections and additional pain organization therapies, and spinal surgery by discectomy via laminotomy or laminectomy and spinal fusion with pedicular screw (6-9). Most conventional therapies are tried before surgery to reduce  the probable complications due to surgical intervention. Indeed, these conservative actions and even operation itself  
with its linked dangers only reduce the symptoms with no influence on the disease procedure in the disc itself. New investigation has given additional vision into the pathogenesis of DDD, which has borne out a transformed attention in biologic therapies positioned on the nucleus pulposus (NP) and the annulus fibrosus and the potential of stem cells to reverse the disease course at a histological and cellular level (10,11).
In this study, we reviewed the existing literature concerning biologic therapies in the regeneration of the intervertebral disc (IVD). We defined the course of stem cell-mediated modalities in treatment of degenerative lumbar disc herniation.
Methods and Materials
Literature search was performed in electronic databases PUBMED and EMBASE by means of MeSH terminologies (nucleus pulposus, therapeutics, annulus fibrosus (AF), intervertebral disc) and keywords in English (degenerative disk disease, stem cells, therapy). The papers published from 1869 to 2016 were considered in this study. Exclusion criteria were trainings available in every language other than English. We studied 61 articles from January 1976 to December 2015.
Intervertebral Disc: Organization and Degeneration
The IVD is avascular and contains predominantly a macromolecular extracellular matrix (ECM) through a low-density populace of cells that aids in preserving this ECM. Obviously, a usual IVD involves a dominant NP enclosed by the AF, all of which intersect each other among two cartilaginous endplates (EPs) (12). The NP is comparatively fluid, composed mainly of an ECM of collagen type II and proteoglycans. Functionally, the collagen provides tensile strength, whereas the proteoglycans bind water, providing flexibility to compression. 
Frequently, the constancy of the NP is defined as “gell mass.” In turn, the AF is collected as a sequence of concentric rings (lamellae) which is chiefly collagen I. The high fraction of collagen marks the AF rigid, a property that assists to contain more fluid NP and make the disc integrated. Lastly, the endplates differentiate the NP and AF from the contiguous vertebral bone. Histologic evaluation has revealed that disc degeneration ultimately initiates in the early teenage years (14,15). The discs of the lumbar spine tolerate an unequal quantity of this wear (14). In IVD degeneration, the rate of matrix anabolism reduces, while matrix catabolism increases. This leads to an amount of variations. Proteoglycan contents in the NP drops meaningfully as well as the capability of the ECM to attract water (16). The amount of chondrocytes in the ECM drops (15,17). Macroscopically, fibrous tissue forms in the NP, and eventually leads to a failure to make distinction between NP and AF (2). Repetitive mechanical loading (18,19) and deteriorating nutrition (18,20,21) have been concerned as the two most critical influences in degeneration. Inadequate nutrition is important in slowing matrix anabolism. Because the IVD is avascular, it needs to obtain nutrients through diffusion. Blood vessels terminate at the EP and nutrients then move based on gradients across the plate and through the ECM to spread in embedded cells. It is well recognized that the EPs develope less permeability by age (21,22), and Boos et al. (2002) found histologic confirmation that a reduction in endplate blood vessels accords with a growth in disc ECM failure. On disc nutrition, it have been recommended that glucose is the serious nutrient for preserving cell viability, with oxygen and pH acting as secondary factors (19,23). Once nutrition of the disc is adequately impaired, disturbance of matrix synthesis and cell death can happen (24,25). The additional factor in disc degeneration is collapse of the matrix. Matrix metalloproteinases (MMPs) and aggrecanases are two enzymes involved in both normal matrix turnover and degeneration. These enzymes destroy the components of the ECM and have been originated at raised levels in degenerated discs (26,27).
Developing Treatments
In current years, treatments directing numerous molecular and cellular features of degeneration have been discovered. One method has been the direct injection or stimulation through gene therapy of an amount of growth factors regulating matrix anabolism (28,29). This practice has revealed hopeful consequences in vitro and in vivo in small animal models (30,31). An alternative major path of study has been cell therapy. The main objective of cell therapy is to increase ECM synthesis via rebuilding the degenerated NP. To achieve this, one
of the numerous types of cells is injected directly into the NP. 
The used cell kinds include NP cells (32), chondrocytes (33), and mesenchymal stem cells (MSCs) (34), all of which have showed potentials for decelerating and repairing degeneration.
Mesenchymal Stem Cells
Transforming growth factor-β3 (TGF-β3) is a factor that has been shown in multiple studies to stimulate cells to differentiate into chondrocytes (35). Several studies have shown that after TGF-β3 stimulation, MSCs turned positive for collagen type II protein and expressed a large panel of genes characteristic for chondrocytes, such as aggrecan, decorin, fibromodulin, and cartilage oligomeric matrix protein (35). Shen et al. (2009) have shown that bone morphogenic protein-2 (BMP-2) can help to enhance TGF-β3-mediated chondrogenesis in MSCs (36). The combination of BMP-2 and TGF-β3 in alginate culture was found to be superior to the standard differentiation method using TGF-β3 alone as evidenced by increased mRNA expression of aggrecan, type II collagen, Sox-9, BMP-2, and BMP-7, all of which are chondrocyte markers. This effect was even more pronounced when TGF-β3 and rhBMP-2 were both added (37). This synergistic effect was consistently found in the study, providing further support as yet unknown pathway towards chondrocytic differentiation.
Embryonic Stem Cells
Hoben et al. (2009) performed a similar characterization study using human ESCs (38). Growth factors were studied with a coculture method for three weeks and evaluated for collagen and glycosaminoglycan (GAG) synthesis. The growth factors studied were TGF-β3, BMP-2, BMP-4, BMP-6, and sonic hedgehog protein. The investigators found that the combination of  BMP-4 and TGF-β3 within th fibrochondrocyte coculture led to an increase in cell proliferation and GAG production compared to treatment alone. Koay et al. (2007) had similar results with BMP-2 and TGF-β3 leading human ESCs down a differentiation path that produced an end product with high type I collagen content (39). However, they also found that human ESCs treated with TGF-β3 followed by TGF-β1 and insulin-like growth
factor-1 (IGF-1) produced constructs with no collagen I, showing that different growth factor application in different temporal sequences can have a marked impact on end-product composition and biomechanical properties. 
Practice in Disc Degeneration
Some in vivo studies have indicated the usage of MSCs to deliberate the course of IVD degeneration and redevelop the matrix. In 2003, Sakai et al. conducted the first study of using the MSCs to restoration of IVD degeneration in vivo using a rabbit model (40). Incomplete aspiration of the NP was used to encourage degeneration, and autologous MSCs were fixed in an atelocollagen gel stayed then inserted into discs. This process was established to avoid histological and morphological disc degeneration while matched to a nontreated, degeneration-induced  controller. General NP and AF construction, cell volume, and matrix development were kept up to eight weeks after injection, and fixed MSCs were found to have differentiated into cells approximating original disc cells. By a rabbit model, Zhang et al. (2008) established that transplanted allogenic MSCs survived and augmented proteoglycan and collagen II synthesis in the NP (41). Wei et al. (2009) used a rat model to evaluate the capability of human MSCs to proliferate and function inside the IVD (42). After six weeks, MSCs confirmed survival and differentiation to disc cells. Extensive success using allogeneic and xenogeneic MSCs may replicate the immune advantage of the IVD (43), like the immunosuppressive abilities of MSCs (44). Henriksson et al. (2009) inserted human MSCs into porcine 
discs which were then gathered at up to six months (45).
At follow-up, MSCs survived and differentiated toward disc cells, displaying matrix-producing functionality. Likewise, Hiyama et al. (2008) found MSC injection into degeneration-induced canine discs proliferated proteoglycan contents and successfully alleviated degeneration (46).
Future Instructions
Combination therapy, providing supportive matrix and bioactive materials, might almost be the finest solution required, improving cell survival, proliferation, and differentiation (47). Numerous growth factors in earlier studies have been implicated in IVD degeneration and therapy. MSCs secreting TGF-β, IGF-1, and platelet-derived growth factor (PDGF) have been established in cocultures with NP cells and have been revealed to be actual stimulators on matrix metabolism and cell proliferation throughout biological reparation of IVDs (48). Growth and differentiation factor- 5 have been exposed to rise disc stature and stimulate proliferation and matrix synthesis in the NP and AF.
Additionally, Henriksson et al. (1997) found endogenous stem cell places in the AF boundary to the ligament zone and the perichondrium area (49). The application of growth factors can excite proliferation of these endogenous stem cells. Immunogenicity, architectural and mechanical properties alongside biocompatibility, biodegradability, and technique of graft transfer should be measured while selecting the scaffold (50). Pharmaceutical studies will similarly require to be complete in order to regulate the cell density and volume that need to be transplanted in order to gain the anticipated outcome, though causing the least quantity of side effects. Given that the IVD is identified as an immunoprivileged organ, the need to discover an autologous cell origin might not be essential (51).
Other important issue is the perfect culture circumstances of the MSCs. First of all, for clinical trials it must be done in good manufacturing practice (GMP) situations with xeno-free substances (48). It is significant to consider that in vitro development can lead to an accumulation of genetic and epigenetic fluctuations by an unknown result in vivo when transplantation is done. The changes might lead to augmented immunogenicity even in autologous or malignant transformation.
It is obvious that there are numerous problems left unanswered. In order to define an actual therapeutic choice for IVD degeneration associated back pain, further designed studies are required. One of the chief problems is making an animal model that can sufficiently duplicate the microenvironment perceived in IVD degeneration. When an animal model is recognized, 
more preclinical records  in a focused method will be available. 
Conflicts of Interest
The authors have no conflicts of interest.

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Type of Study: Research |
* Corresponding Author Address: *Corresponding Author Address: Department of Neurosurgery, Imam Khomeini Hospital, Orthopedic Research Center, Mazandaran University Of Medical Sciences, Sari, Mazandaran, Iran. E mail:kh568hd@yahoo.com, Tel/Fax number: +98-11-33378789, Postal code: 48166

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