Current Stem Cell Research & Therapy - Volume 10, Issue 4, 2015

As a main contributing factor to low back pain, intervertebral disc degeneration (IDD) is the fundamental basis for various debilitating spinal diseases. The pros and cons of current treatment modalities necessitate biological treatment strategies targeting for reversing or altering the degeneration process in terms of molecules or genes. The advances in stem cell research facilitate the studies aiming for possible clinical application of stem cell therapies for IDD. Human NP cells are versatile with cell morphology full of variety, capable of synthesizing extracellular matrix components, engulfing substances by autophagy and phagocytosis, mitochondrial vacuolization indicating dysfunction, expressing Fas and FasL as significant omens of immune privileged sites. Human discs belong to immune privilege organs with functional FasL expression, which can interact with invasive immune cells by Fas-FasL regulatory machinery. IDD is characterized by decreased expression level of FasL with dysfunctional FasL, which in turn unbalances the interaction between NP cells and immune cells. Certain modulation factors might play a role in the process, such as miR-155. Accumulating evidence indicates that Fas-FasL network expresses in a variety of stem cells. Given the expression of functional FasL and insensitive Fas in stem cells (we term as FasL privilege), transplantation of stem cells into the disc may regenerate the degenerative disc by not only differentiating into NP-like cells, increasing extracellular matrix, but also reinforce immune privilege via interaction with immune cells by Fas-FasL network.

Intervertebral disc (IVD) degeneration is one of the leading causes of low back pain, which affects a large proportion of the global population at a huge socioeconomic burden. Current treatments focus primarily on symptomatic pain relief or surgery, but offer relatively poor long-term efficacy as they fail to address the pathogenesis of the underlying IVD degeneration. In order to offer improved clinical outcomes, a number of biological and regenerative therapies are currently being developed which target the disease at a molecular and cellular level and aim to restore IVD function. This review focusses on the considerations for development of cell-based therapies for IVD regeneration. In particular it focusses on the identification of novel progenitor cell populations within the IVD and the application of mesenchymal stem cells (MSCs) in IVD tissue engineering, which are being increasingly studied as they offer huge potential for tissue regeneration. Additionally it highlights how the growing understanding of the molecular phenotype of IVD cells is allowing tailored differentiation strategies to be developed and how MSC source and choice of growth factor influences cell phenotype and appropriate tissue formation. Finally, it reviews the range of functional biomaterials being developed to aid MSC delivery and differentiation, and discusses the potential impact the degenerate IVD microenvironmental niche may have on MSC behaviour following implantation

Intervertebral disc (IVD) degeneration and associated low back pain (LBP) remains a major burden to our society without significant improvements in treatment strategies or patient’s quality of life. While the recent cell-transplantation studies for treatment of degenerative disc disease have shown promising results, to better gauge the success and functional outcomes of these therapies, it is crucial to understand if transplanted cells give rise to healthy nucleus pulposus (NP) tissue. NP cell phenotype is unique and is defined by expression of a characteristic set of markers that reflect specialized physiology and function. This review summarizes phenotypic markers that mirror the unique physiology and function of NP cells and their progenitors and should be considered to when measuring outcomes of cell-based therapies to treat disc degeneration.

Intervertebral disc degeneration is directly linked to chronic low back pain, a condition that affects multitudes of people world-wide and presents tremendous direct and indirect health costs. Water- loss, inflammation and disruption of the extracellular matrix ultimately result in loss of tissue function and associated pain. Cytokines present in degenerate tissue can upregulate protease activity and directly causes pain. Non-invasive therapies provide limited efficacy for pain management, and surgical intervention is therefore often required to treat chronic low back pain. Disc removal can offer immediate pain-relief, however degeneration of adjacent segments can occur and pain can return. To circumvent the caveats of recurring pain and invasive surgeries, stem cell therapy is currently being investigated as a promising means to repair degenerating discs. However, while initial studies have shown promise, few studies have addressed whether stem cell therapies can modulate the inflammatory microenvironment or whether cytokines can affect the ability of the implanted cells to repair damaged tissue. This review focuses briefly on mechanisms of disc degeneration, with more attention given to the role of inflammatory milieu in this process. Cytokine upregulation in disc degeneration, the potential role of tolllike receptor signaling, and effects of these inflammatory factors on stem cells will be discussed. We find that while stem cell differentiation can be negatively influenced by inflammatory cytokines, stem cells can potentially have antiinflammatory effects. We conclude that further investigation of stem cell interactions with the inflammatory microenvironment is required, and that priming of stem cells under various conditions may be necessary for optimal therapeutic value for intervertebral disc repair and pain reduction.

Intervertebral disc (IVD) disorders, especially degenerative disc disease, reduce the quality of life, and are short of effective therapy. A new direction for treatment of chronic tissue and organ diseases is to promote regeneration by harnessing endogenous repair mechanisms. In this review, we discuss the potential of endogenous repair in the IVD, the recent findings on endogenous IVD progenitor cells, and stem cell niches involved in IVD endogenous repair. We also highlight the factors which may restrict IVD self-healing. Ultimately, advanced therapeutic attempts to boost endogenous repair in the IVD are discussed, including bioactive factor delivery, gene therapy, activation of endogenous IVD progenitor cells and chemokine mediated stem cell homing.

In recent decades the application of bioreactors has revolutionized the concept of culturing tissues and organs that require mechanical loading. In intervertebral disc (IVD) research, collaborative efforts of biomedical engineering, biology and mechatronics have led to the innovation of new loading devices that can maintain viable IVD organ explants from large animals and human cadavers in precisely defined nutritional and mechanical environments over extended culture periods. Particularly in spine and IVD research, these organ culture models offer appealing alternatives, as large bipedal animal models with naturally occurring IVD degeneration and a genetic background similar to the human condition do not exist. Latest research has demonstrated important concepts including the potential of homing of mesenchymal stem cells to nutritionally or mechanically stressed IVDs, and the regenerative potential of “smart” biomaterials for nucleus pulposus or annulus fibrosus repair. In this review, we summarize the current knowledge about cell therapy, injection of cytokines and short peptides to rescue the degenerating IVD. We further stress that most bioreactor systems simplify the real in vivo conditions providing a useful proof of concept. Limitations are that certain aspects of the immune host response and pain assessments cannot be addressed with ex vivo systems. Coccygeal animal disc models are commonly used because of their availability and similarity to human IVDs. Although in vitro loading environments are not identical to the human in vivo situation, 3D ex vivo organ culture models of large animal coccygeal and human lumbar IVDs should be seen as valid alternatives for screening and feasibility testing to augment existing small animal, large animal, and human clinical trial experiments.

Background: The successful surgical restoration of damaged meniscus has been a challenge, largely owing to a lack of characterization of meniscus cells and their precursors. Numerous strategies to repair or replace meniscus have achieved only limited success. Several recent studies have shown beneficial effect of mesenchymal stem cells in meniscus repair. The objective of our study was to characterize meniscus derived mesenchymal stem cells in terms of, colony formation, proliferation, multi potency and self-renewal capacity. Methods: Mesenchymal stem cells were isolated from menisci, patellar tendon and bone marrow of rabbits. The multi differentiating potential, colony, morphology and proliferation were studied in vitro. The expression of differential markers was studied by immunocytochemistry, qPCR and western blotting. Results: Three groups of cells appeared similar in colony formation and morphology. All of them were found to express high levels of stem cell markers including SSEA-4, Nanog and nucleostemin. High level of collagen II expression was detected in meniscus derived stem cells. Moreover, these cells appeared to have a pronounced tendency to chondrogenic differentiation under specialized culture conditions. Conclusions: Meniscus-derived mesenchymal stem cells (MMSCs) possessed all the necessary criteria of stem cells, including clonogenicity, self-renewal and multipotent differentiation capacity and possessed a tendency to differentiate into chondrocytes. Our results offer new insights into the biology of meniscus cells, and may assist in future strategies to treat damaged meniscus.

Coronary artery disease (CAD) is a significant global health problem, contributing to significant morbidity and mortality. Percutaneous coronary intervention (PCI) is an efficient therapy for treating CAD, but it carries the risk of iatrogenic endothelial injury, which contributes to vessel inflammation and induction of in-stent restenosis. Therefore, developing novel methods for enhancing re-endothelialization after PCI is highly needed. Endothelial progenitor cells (EPCs) can differentiate into mature endothelial cells, and cell therapy with EPC may offer a novel way for accelerating reendothelialization. In this review paper, we aimed to briefly describe EPCs and highlight their potential therapeutic roles in in-stent re-stenosis and endothelial injury.