The nucleus pulposus microenvironment in the intervertebral disc: the fountain of youth?

Abstract

The intervertebral disc (IVD) is a complex tissue, and its degeneration remains a problem for patients, without significant improvement in treatment strategies. This mostly age-related disease predominantly affects the nucleus pulposus (NP), the central region of the IVD. The NP tissue, and especially its microenvironment, exhibit changes that may be involved at the outset or affect the progression of IVD pathology. The NP tissue microenvironment is unique and can be defined by a variety of specific factors and components characteristic of its physiology and function. NP progenitor cell interactions with their surrounding microenvironment may be a key factor for the regulation of cellular metabolism, phenotype, and stemness. Recently, celltransplantation approaches have been investigated for the treatment of degenerative disc disease, highlighting the need to better understand if and how transplanted cells can give rise to healthy NP tissue. Hence, understanding all the components of the NP microenvironment seems to be critical to better gauge the success and outcomes of approaches for tissue engineering and future clinical applications. Knowledge about the components of the NP microenvironment, how NP progenitor cells interact with them, and how changes in their surroundings can alter their function is summarised. Recent discoveries in NP tissue engineering linked to the microenvironment are also reviewed, meaning how crosstalk within the microenvironment can be adjusted to promote NP regeneration. Associated clinical problems are also considered, connecting bench-to-bedside in the context of IVD degeneration.

Consolidating and re‐evaluating the human disc nutrient microenvironment

“…Together these have established the conjecture that NP glucose concentrations are critically low, making it particularly inhospitable to potential cell therapies. 58 , 59 , 120 Although it is important to note that each of these studies investigated effects such as reducing nutrient supply or exchange area 69 , 75 and altering tissue diffusivity, 69 , 71 , 72 particularly through reducing CEP permeability or porosity through parametric analysis. 73 , 74 , 77 Other osmo‐mechanical properties include altering water content, fixed charge, deformation, 70 , 74 and dynamic loading.…”

“…Acidity has been shown to be important for maintaining NP cell activity. 59 However, too low a pH is detrimental for proteoglycan (PG) synthesis rates which have been seen to reduce significantly below pH 6.8. 41 , 109 , 115 Hence, it is vital to consider the in vivo pH microenvironment at difference stages of degeneration in developing a cell therapy to survive and reach full regenerative capacity within the patient's specific microenvironment.…”

“…However, studies have used lower hypoxic concentrations of 0.1‐1 %O 2 and a higher concentration of 10 %O 2 . 27 , 29 Although lower oxygen appears to provide optimal functioning for native NP cells and some potential cell sources, 59 , 132 hypoxia, and matrix acidity are also linked to the progression of a pro‐inflammatory microenvironment, 133 , 134 in particular, interleukin‐1 β (IL‐1β) and tumor necrosis factor‐α (TNF‐α) which are believed to be critical in inducing degeneration of the ECM through cell senescence and upregulation of matrix metalloproteinases (MMPs). 135 , 136 Therefore, we need to consolidate what “ physioxia” means in terms of the IVD microenvironment and re‐evaluate the culturing conditions used in vitro.…”

“… 9 , 11 , 57 , 58 In total, 16 clinical trials investigating cell‐based therapies have been registered worldwide for IVD degeneration and although they demonstrate the procedures to be safe, clinical evidence of positive efficacy remains unclear. 8 , 54 , 55 , 59 , 60 To fully realize these strategies and maximize clinical translation of cell‐based therapies, there is an urgent need to consolidate what is already known regarding the in vivo nutrient microenvironment.…”

Mesenchymal Stem Cell-Derived Exosomes: The New Frontier for the Treatment of Intervertebral Disc Degeneration

“…The harsh microenvironment with the absence of vasculature, hypoxia, low glucose concentration, acidity, hyperosmolarity and continuous mechanical stimulation plays a crucial role for cell survival and their regenerative potential [61]. Furthermore, MSC implantation may further impair the balance between the nutrient supply and demand of resident disc cells, thus causing cell death.…”