https://www.kau.edu.sa/Files/117/Researches/67223_38723.pdf

Mesenchymal stem cells in regenerative medicine: Focus on articular cartilage and intervertebral disc regeneration

Defects of load-bearing connective tissues such as articular cartilage and intervertebral disc (IVD) can result from trauma, degenerative, endocrine, or age-related disease. Current surgical and pharmacological options for the treatment of arthritic rheumatic conditions in the joints and spine are ineffective. Cell-based surgical therapies such as autologous chondrocyte transplantation (ACT) have been in clinical use for cartilage repair for over a decade but this approach has shown mixed results. This review focuses on the potential of mesenchymal stem cells (MSCs) as an alternative to cells derived from patient tissues in autologous transplantation and tissue engineering. Here we discuss the prospects of using MSCs in regenerative medicine and summarize the advantages and disadvantages of these cells in articular cartilage and IVD tissue engineering. We discuss the conceptual and practical difficulties associated with differentiating and pre-conditioning MSCs for subsequent survival in a physiologically harsh extracellular matrix, an environment that will be highly hypoxic, acidic, and nutrient deprived. Implanted MSCs will be exposed to traumatic physical loads and high levels of locally produced inflammatory mediators and catabolic cytokines. We also explore the potential of culture models of MSCs, fully differentiated cells and co-cultures as "proof of principle" ethically acceptable "3Rs" models for engineering articular cartilage and IVD in vitro for the purpose of replacing the use of animals in arthritis research.

/pdf/mesenchymal-stem-cells-in-regenerative-medicine-1mvh21y89t.pdf

Mesenchymal stem cells in regenerative medicine: opportunities and challenges for articular cartilage and intervertebral disc tissue engineering.

Loading is important to maintain the balance of matrix turnover in the intervertebral disc (IVD). Daily cyclic diurnal assists in the transport of large soluble factors across the IVD and its surrounding circulation and applies direct and indirect stimulus to disc cells. Acute mechanical injury and accumulated overloading, however, could induce disc degeneration. Recently, there is more information available on how cyclic loading, especially axial compression and hydrostatic pressure, affects IVD cell biology. This review summarises recent studies on the response of the IVD and stem cells to applied cyclic compression and hydrostatic pressure. These studies investigate the possible role of loading in the initiation and progression of disc degeneration as well as quantifying a physiological loading condition for the study of disc degeneration biological therapy. Subsequently, a possible physiological/beneficial loading range is proposed. This physiological/beneficial loading could provide insight into how to design loading regimes in specific system for the testing of various biological therapies such as cell therapy, chemical therapy or tissue engineering constructs to achieve a better final outcome. In addition, the parameter space of ‘physiological’ loading may also be an important factor for the differentiation of stem cells towards most ideally ‘discogenic’ cells for tissue engineering purpose.

/pdf/the-effects-of-dynamic-loading-on-the-intervertebral-disc-18bojbocn6.pdf

The effects of dynamic loading on the intervertebral disc

Mechanical factors play a crucial role in the development of articular cartilage in vivo. In this regard, tissue engineers have sought to leverage native mechanotransduction pathways to enhance in vitro stem cell-based cartilage repair strategies. However, a thorough understanding of how individual mechanical factors influence stem cell fate is needed to predictably and effectively utilize this strategy of mechanically-induced chondrogenesis. This article summarizes some of the latest findings on mechanically stimulated chondrogenesis, highlighting several new areas of interest, such as the effects of mechanical stimulation on matrix maintenance and terminal differentiation, as well as the use of multifactorial bioreactors. Additionally, the roles of individual biophysical factors, such as hydrostatic or osmotic pressure, are examined in light of their potential to induce mesenchymal stem cell chondrogenesis. An improved understanding of biomechanically-driven tissue development and maturation of stem cell-based cartilage replacements will hopefully lead to the development of cell-based therapies for cartilage degeneration and disease.

/pdf/mechanical-regulation-of-chondrogenesis-1jgna58fiv.pdf

Mechanical regulation of chondrogenesis

The effects of microenvironment in mesenchymal stem cell–based regeneration of intervertebral disc

Low back pain is the most common cause of activity limitation in people younger than 45 years and the second most frequent reason for visits to the physician. In addition, low back pain is the fifth-ranking cause of admission to the hospital, and the third most common cause of surgical procedures in the United States.1 Therefore, costs for the health care system due to low back pain is estimated to be 100 billion dollars.2 Low back pain is a multifactorial crisis, and intervertebral disc (IVD) degeneration plays an important role in its epidemiology.3-5 Recent approaches for biologic repair and regeneration of the IVD are under investigation including cell transplantation, administration of growth factors, and gene therapy.6,7 Mesenchymal stem cells (MSCs) may be ideal candidates for cell therapies and tissue engineering because of their high proliferation rate8 and potential for multilineage differentiation.9

The microenvironmental niche, characterized by the niche cells itself and their chemical and physical environment, has a strong influence on MSC behavior and differentiation.10 The harsh microenvironment of IVDs can influence resident cells negatively, and may be particularly critical for MSCs that might be implanted in the IVD. The response of MSCs to the microenvironmental conditions of the IVD under healthy and degeneration conditions is largely unknown, and it is not clear which factors, if any, are critical to successful MSC survival, proliferation, and differentiation. The IVD microenvironment has distinct and extreme chemical characteristics that are the focus of this study, including reduced nutrition, high extracellular osmolarity, and acidic pH.

The response of IVD cells to microenvironmental conditions has been partially explored,11-20 but very few studies investigated MSCs in the IVD niche.21,22 Further, there is some evidence that the potential of MSCs may depend on the donor's age, although this has not been tested so far with regards to approaches for the IVD. Recent studies were able to show that their potential for differentiation and proliferation may be higher in younger donors compared with older donors.23-25

The aim of this study was to investigate effects of the chemical conditions representative of a healthy or mildly degenerated IVD on proliferation, viability, and gene expression of MSCs. We hypothesized certain IVD-like conditions will increase biosynthesis rates and proliferation whereas others will inhibit expression of important matrix proteins and also reduce MSC viability and proliferation. We also hypothesized MSCs harvested from young rats will be more adaptable to the IVD chemical niche than MSCs from mature rats.

/pdf/behavior-of-mesenchymal-stem-cells-in-the-chemical-23k5dfpvzg.pdf

Jocelyn Urban

Papers

Behavior of mesenchymal stem cells in the chemical microenvironment of the intervertebral disc.