Abstract
ABSTRACTBackgroundMesenchymal stem cells (MSCs) are becoming an increasingly attractive option for regenerative therapies due to their availability, self‐renewal capacity, multilineage potential, and anti‐inflammatory properties. Clinical trials are underway to test the efficacy of stem cell‐based therapies for the repair and regeneration of the degenerate intervertebral disc (IVD), a major cause of back pain. Recently, both bone marrow‐derived MSCs and adipose‐derived stem cells (ASCs) have been assessed for IVD therapy but there is a lack of knowledge surrounding the optimal cell source and the response of transplanted cells to the low oxygen, pro‐inflammatory niche of the degenerate disc. Here, we investigated several neurovascular factors from donor‐matched MSCs and ASCs that may potentiate the survival and persistence of sensory nerve fibers and blood vessels present within painful degenerate discs and their regulation by oxygen tensions and inflammatory cytokines.MethodsDonor‐matched ASCs and MSCs were conditioned with either IL‐1β or TNFα under normoxic (21% O2) or hypoxic (5% O2) conditions. Expression and secretion of several potent neurovascular factors were assessed using qRT‐PCR and human magnetic Luminex assay.ResultsASCs and MSCs expressed constitutive levels of key neurotrophic factors; and stimulation of ASCs with hypoxia triggered increased secretion of both angiogenic factors (Ang‐2 and VEGF‐A) and neurotrophic (NGF and NT‐3) compared to MSCs. We also report increased transcriptional regulation of pain‐associated neuropeptides in hypoxia stimulated ASCs compared to those in normoxic conditions. We demonstrate transcriptional and translational upregulation of NGF, NT‐3, Ang‐1, and FGF‐2 in response to cytokines in ASCs in 21% and 5% O2.ConclusionsThis work highlights fundamental differences between the neurovascular secretome of donor‐matched ASCs and MSCs, demonstrating the importance of cell‐selection for tissue specific regeneration to reduce ectopic sensory nerve and blood vessel survival and improve patient outcomes.
Highlights
Mesenchymal stem cells (MSCs) are becoming an increasingly attractive option for regenerative therapies due to their availability, self-renewal capacity, multilineage potential, and anti-inflammatory properties
Ang-1 was significantly upregulated by tumor necrosis factor alpha (TNFα) in MSCs under 5% O2 compared to unstimulated controls at gene level, with similar insignificant increases seen at secreted protein level (Figure 2A,B)
Ang-2 expression was not regulated by cytokines from adipose-derived stem cells (ASCs) or MSCs under 21% oxygen at gene or protein level (Figure 2C,D), yet levels of Ang-2 were significantly higher in ASCs under 5% O2 compared to 21% O2, and cytokines interleukin-1 beta (IL-1β) and TNFα significantly reduced expression of Ang-2 at gene and protein level in ASCs under 5% O2 compared to unstimulated controls (Figure 2C,D)
Summary
Mesenchymal stem cells (MSCs) are becoming an increasingly attractive option for regenerative therapies due to their availability, self-renewal capacity, multilineage potential, and anti-inflammatory properties. Clinical trials are underway to test the efficacy of stem cell-based therapies for the repair and regeneration of the degenerate intervertebral disc (IVD), a major cause of back pain. Total annual costs associated with back pain are estimated in excess of €12 billion across Europe Both the UK and the US report LBP as being the most common cause of disability amongst young adults, leading to a loss of more than 100 and 149 million workdays per year, respectively.[1] It is starkly clear that as the world population ages, the disease burden of LBP will increase substantially. The causes of LBP remain multifactorial, approximately 40% of all cases are attributed to the degeneration of one or more IVDs.[2]
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