Nerve Regeneration Mechanism

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Work full title: Peripheral Nerve Regeneration Mechanism on Granting Conditioned Medium Origin Mesenchymal Stem Cells Umbilical Cord.

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Acute peripheral nerve injury is a trauma to an extremity and a complication that occurs in 3-10% of trauma patients. Research into injury of the 1st, 2nd and 3rd peripheral nerves (Peripheral Nerve Injuries, PNI) is important because these injuries can cause significant disability among young adults, who generally are of working age. Targeted healing of nerve injuries refers to the return of nerve function as it was before the actual injury. Achieving therapeutic nerve function reconstruction involves huge health care costs [4, 5] and extended duration of inpatient and outpatient care. Other associated costs include labor costs such as lost wages and sick leaves. Target nerve injury healing is also dependent on various factors such as age and causative agent of injury [5, 6].

According Raffe et al (1985), the factors that affect the nerve healing are generally divided into two categories, namely extrinsic and intrinsic factors. Extrinsic factors are factors outside the patients control while intrinsic factors are those outside the physicians control. Extrinsic factors include all activities falling within the integrated PNI management pathway, such as surgical techniques employed and selection of suture material and instrumentation.

Intrinsic factors include the patients age, nutritional status, the time and type of the injury, the severity of the injury, extent of neural involvement, and the degree of the nerve regeneration process before clinical presentation [7]. Reinnervation is quite a complex process, involving neurons, microenvironment (niche) and the target. This knowledge is very important so as to inform research into why nerve regeneration often fails to restore nerve function [14]. For instance, peripheral axotomy triggers a variety of remodeling responses such as neuronal node expression of neurotrophins, cytokines and actin. These processes are crucial to the process of axonal regeneration and an understanding of their underlying causative factors is critical to designing stronger supplementary strategies when regenerative processes are ineffective.

Surgical intervention is part of the integrated PNI management of pathway needed to prevent the misdirection of axons that can result in less than optimal therapeutic results. Surgical intervention is also necessary to reduce the width of the gap between the two ends of severed nerves. Injuries to the wide gap requires nerve grafting to minimize nerve gap [12]. While there are a variety of surgical techniques employed in PNI repair, such as use of vein grafts to approximate small axonal gaps of less than 3cm in distance, autologous nerve grafting is the mainstay of surgical nerve repair.

Regardless, repair of nerve injuries continues to be a major challenge in peripheral nerve injury therapy. The normal function of sensory and motor nerves can rarely be achieved despite successful nerve repair and the formation of post-repair neural networks [2, 13-17]. As previously mentioned, PNI management is dependent on extrinsic factors, one of which is a factor of the microenvironment (niche). Tissue microenvironments can be enhanced by administering supportive therapy such as administration of mesenchymal stem cells (MSCs) and / or conditioned medium containing MSCs many growth factors that are important for the regeneration of peripheral nerve injury. Various growth factors secreted by MSCs are thought to have a positive effect on the regeneration of various tissues.

For instance, conditioned medium for MSCs-derived adipose cells has been shown to regenerate hair follicles and conditioned medium-derived MSCs from bone marrow can improve glomerulopathy in diabetics [53]. However, whether conditioned medium of origin of umbilical cord MSCs also has a positive effect on the peripheral nerve regeneration still needs to be proven.

On regeneration and degeneration of peripheral nerves in response to peripheral nerve injury occurred early cell proliferation Schwann [50]. Schwann cell proliferation reaches a maximum of two or three days after the injury. Schwann cells serves to form the myelin and nerve fibers microenvironment. Damage to the peripheral nerves induces differentiation and activation of Schwann cells to produce a variety of factors supporting the growth of axons and remyelinization. Maintenance of the microenvironment of nerve fibers is an important factor in neuronal restoration [18]. Giving amniotic fluid MSCs following peripheral nerve injury is known to increase cell proliferation and increase Schwaan vascularization in areas experiencing growth inhibition [29]. However, whether MSCs-TP has the same capabilities as the origin of the amniotic fluid MSCs is still unknown.

Various supporting factors produced by Schwann cells, among them neurotropin, neuregulatori cytokine, TGF-b, glial cell line-derived neurotrophic factor (GDNF), epirdermal growth factor (EGF) and platelet-derived growth factor (PDGF) [51]. One important function of Schwann cells is to produce nerve growth factor (neural growth factors / NGF) [52,53]. In a study that modeled chronic nerve compression injury, Schwann cells were induced to increase the production of vascular endothelial growth factor (VEGF), which is responsible for increasing the vascularization of nerve blood vessels in response to chronic nerve compression injury [54]. NGF and VEGF are the growth factors associated with the proliferation and migration of Schwann cells and neovascularization. This regenerative response by Schwann cells is critical in improving nerve injury healing [27, 28].

Schwann cells and the extracellular matrix endoneurial play an important role in axon regeneration. A collection of peripheral nerve axons are wrapped in loose connective tissue sheath (endoneurium) called fascicles; each fasciculus is separated by a sheath of connective tissue that is more dense (perineurium), and in the outermost layer all fascicles are wrapped again by dense connective tissue with an irregular arrangement called the epineurium. VEGF gene therapy as reported by Pereira et al can improve the regeneration process by increasing vascularization, restoring myelination and improving nerve function [58].

VEGF as an angiogenic factor that stimulates the proliferation and migration of endothelial cells and, in vivo, can increase the formation of new blood vessels in the connective tissue sheath [59]. Inda et al (2009) reported that VEGF is a potent angiogenic factor correlated with the expression of CD34 protein, an endothelial antigen that is used to determine the density of blood vessels and endothelial marker degrees angiogenesis [60]. Examination of the expression of VEGF and CD34 needs to be done to find out if one of the mechanisms of peripheral nerve regeneration after injury can be through the formation of neovascularization, the knowledge of this mechanism is important to achieve therapeutic results optimal [50].

Mesenchymal stem cells (MSCs) are multipotent mesenchymal stromal that can express themselves on nearly every organ and tissue MSCs pascanatal [26]. For therapeutic purposes, MSCs can be isolated from bone marrow, umbilical cord, amniotic fluid or other tissue. Some studies have suggested the use of MSCs as a method of alternative therapies because it has the ability for differentiation. Mesenchymal stem cells can differentiate into a variety of cells in the nervous system, such as astrocytes, oligodendrocytes and Schwann cells.

A study into the ability of MSCs to differentiate noted that in vitro MSCs derived from umbilical cord Wharton's Jelly able to differentiate into Schwann cells. The medium used for the differentiation of these stem cells is DMEM medium containing b-mercaptoethanol, Fetal bovine serum (FBS), trans retinoic acid, platelet derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) isolated from human subjects. Immunocytochemistry is also used in the study. Cells grown on media were labeled with Hoechst33258 berinkorporasi the cell nucleus. Cells grown were also tinged with Schwann cell markers, namely S100, GFAP and p75. In another study, MSCs were grown on a medium of propagation and given another label- BrdU- to see proliferation [54, 55].

The umbilical cord as a source of MSCs is relatively easy to obtain and there exist non-invasive methods of uptake. Extracting MSCs from umbilical cord is non-controversial and no ethical constraints arise, unlike in the case of embryonic stem cells. MSCs are multipotent stem cells and have the capacity to improve themselves and to differentiate into various cell types of mesodermal lineage [31]. As a source of allogeneic cells, MSCs-TP can be antigenic on the receiver. However, in a different study, TP MSCs were demonstrated to possess low immunogenicity and are imunospresan. The study mentions that MSCs TP expressing MHC-I did not express MHC II and costimulatory molecules CD80 (B7-1), CD86 (B7-2), CD40, and CD40 ligand, which is mainly expressed on antigen -presenting cells (APC) and a variety of tissue cells. The study mentions that MSCs-TP do not induce adverse reactions to cell alogenik [55]. These results demonstrate the immunogenicity of MSCs-TP is low. In another study, laboratory mice with burns were treated with human-derived TP MSCs [56].

Stem cells of umbilical cord mesenchymal origin (MSCs-TP) is said to secrete a variety of growth factors including NGF and VEGF are important to support Schwann cell proliferation [15]. Potential MSC therapy can be significantly improved by adding growth factors (for example, combining cell and gene therapy ). The merger of therapy and MSCs, which secrete bFGF, PDGF and VEGF, is demonstrated in another study. In the study, it is shown that the combination may affect the biology of the cells and increase proliferation of MSC and change their differentiation potential. Furthermore, VEGF expression does not differ from controls in terms MSC proliferation or differentiation test, but has the potential for significantly greater angiogenic activity in vitro and in vivo, indicating that this may be a safe and effective strategy for treating vascular complications.

Research Ghiasi (2014) mentions that MSCs grown in vitro do not only have the ability to respond to stimuli and differentiate but can also serve as a secretory agent for most of the growth factors and cytokines such as MCP-1 (monocyte chemotactic protein-1), VEGF -A, EGF (epidermal growth factor), FGF-2, IL-6 (Interleukin 6), LIF (Leukemia Inhibitory factor), TGF-ss (transforming growth factor beta) into the medium, and the medium containing the growth factor a...

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