Introduction
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.

Results
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. 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.

Conclusion
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. 

Funding
None.

Conflicts of Interest
The authors have no conflicts of interest.


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