The effect of extracellular acidosis on the behaviour of mesenchymal stem cells in vitro

Abstract

The stem cell fraction of a cell population is finely tuned by stimuli from the external microenvironment. Among these stimuli, a decrease of extracellular pH (pHe) may occur in a variety of physiological and pathological conditions, including hypoxia and inflammation. In this study, by using bone marrow stem cells and dental pulp stem cells, we provided evidence that extracellular acidosis endows the maintenance of stemness in mesenchymal cells. Indeed, continuous exposure for 21 d to low pHe (6.5-6.8) conditions impaired the osteogenic differentiation of both cell types. Moreover, the exposure to low pHe, for 1 and up to 7 d, induced the expression of stemness-related genes and proteins, drove cells to reside in the quiescent G0 alert state and enhanced their ability to form floating spheres. The pre-conditioning with extracellular acidosis for 7 d did not affect the differentiation potential of dental pulp stem cells since, when the cells were cultured again at physiological pHe, their multilineage potential was almost unmodified.Our data provided evidence of the role of extracellular acidosis as a modulator of the stemness of mesenchymal cells. This condition is commonly found both in systemic and local bone conditions, hence underlining the relevance of this phenomenon for a better comprehension of bone healing and regeneration.

Potassium citrate prevents increased osteoclastogenesis resulting from acidic conditions: Implication for the treatment of postmenopausal bone loss

“…By itself, the acidic milieu favors the dissolution of bone matrix [11], but, also, it may alter some cell functions involved in the mineralization process. In agreement with literature data, we found that pH 6.9 decreases ALPL and Runx2 expression [57], induces a slight increase in OPG, while collagen and BGLAP were not affected [5,58,59]. Alkaline phosphatase plays a pivotal role in regulating bone mineralization, since it catalyzes the inorganic pyrophosphate (PPi) hydrolysis and provides inorganic phosphate (Pi) for the nucleation of hydroxyapatite crystals [60].…”

Understanding and leveraging cell metabolism to enhance mesenchymal stem cell transplantation survival in tissue engineering and regenerative medicine applications

“…Although less detrimental than glucose shortage, lower intracellular and extracellular pH levels inhibit MSC metabolism, proliferation, and osteogenic differentiation. [77][78][79][80][81][82][83] Acidifying the extracellular medium of rabbit MSCs to pH 6.8-7.0 resulted in large decreases in the glucose consumption rate and the lactate production rate (48.3% and 95.1%, respectively), compared with standard cell culture conditions at pH >7.4. 78 This finding suggests a reduction in glycolysis, which may be a feedback system to avoid further acidification of the extracellular space that would ultimately lead to an excessive acidification of the cytosol and cell death.…”

“…78 This finding suggests a reduction in glycolysis, which may be a feedback system to avoid further acidification of the extracellular space that would ultimately lead to an excessive acidification of the cytosol and cell death. 77,78 Moreover, Massa et al 81 Consequently, research should refocus its effort to rationally engineer a new generation of cell-containing scaffolds that provide nutrients tailored to the needs of transplanted cells. Given that glucose (and not oxygen) is essential to ensure MSC survival via glycolysis, 29,30,57 recent strategies have focused on delivering this chemical compound to cells.…”

Lactate in Sarcoma Microenvironment: Much More than just a Waste Product

“…Moreover, several studies report that subsequently to MSC recruitment, tumor tissues educate MSCs to adopt a tumor-growth promoting phenotype [13]. In response to tumor derived acidity, resident MSCs are reprogrammed to tumor tissue-derived MSCs (t-MSCs), which further increase local acidification sustaining tumor progression [14,15]. Several studies demonstrated that MSCs induce pro-proliferative effects on tumor cells, promote OS stemness and epithelial to mesenchymal transition (EMT), recruit immunosuppressive cells and support tumor angiogenesis [16,17].…”

“…Furthermore, MSCs-stimulated OS cells increase the expression of pro-angiogenetic factors and promote migration, invasion and formation of the capillary network of endothelial cells in vitro [18]. Moreover, between MSCs and sarcoma cells a strict cross-talk is established: really, local tumor-derived acidosis, as well as, tumor associated osteolysis exert a great impact on MSC stemness [14,15]. Also lactate, the main driver of tumor acidosis, has a key role in OS progression: Bonucelli G. et al demonstrated that MSCs are induced by adjacent OS cells to undergo Warburg metabolism and hence to increase lactate production and monocarboxylate transporter 4 (MCT4) expression.…”