Abstract
The simultaneous increases in blood lactic acid and erythrocytes after intense exercise could suggest a link between lactate and the erythropoiesis. However, the effects of lactic acid on erythropoiesis remain to be elucidated. Here, we utilized a mouse model to determine the role of lactic acid in this process in parallel with studies using leukaemic K562 cells. Treatment of K562 cells in vitro with lactic acid increased the mRNA and protein expression of haemoglobin genes and the frequency of GPA+ cells. Also, increases in haematocrit and CD71−/Ter119+ erythroid cells were observed in lactic acid-treated mice, which showed a physiological increase in blood lactate. Mouse bone marrow CD34+/CD117− cells showed an increase in erythroid burst-forming units after stimulation with lactic acid in vitro. Furthermore, lactic acid increased the intracellular reactive oxygen species (ROS) content in bone marrow and in K562 cells. Erythroid differentiation induced in Haematopoietic Stem Cells (HSCs) and K562 cells by lactic acid was abolished by reducing ROS levels with SOD or 2-mercaptoethanol, which suggests that ROS is a critical regulator of this process. These findings provide a better understanding of the role of lactic acid in cellular metabolism and physiological functions.
Highlights
Erythrocytes function to transport oxygen to tissues and are essential for the survival of all vertebrate animals
These results suggest that suitable lactic acid concentrations promote the generation of erythroid burst-forming-unit erythroid (BFU-E) progenitors and the maturation of erythroid cells, whereas high doses of lactic acid may be toxic to normal bone marrow (BM) cells but still can induce the erythropoiesis (Fig. 2b)
We found that lactic acid was able to differentiate the human leukaemia cell line K562 towards erythroid cell lineages
Summary
Erythrocytes function to transport oxygen to tissues and are essential for the survival of all vertebrate animals. Erythropoiesis is a complex multistep developmental process that mainly occurs in the bone marrow during adulthood in humans, including multipotent hematopoietic stem cells (HSCs) differentiate, proliferate, and mature into red blood cells[1,2,3]. The commitment of HSCs to an erythroid lineage requires glutamine metabolism and glutamine-dependent de novo nucleotide biosynthesis Blocking this pathway could divert HSCs towards cells with myelomonocytic fates[9]. Lactic acid increases synchronously with erythropoiesis in some physiologically and pathologically hypoxic conditions, such as during intense exercise, long periods at high altitudes[17], and in cancer patients with various types of tumours[18,19]. Our data demonstrate that lactic acid promoting erythroid differentiation by intracellular ROS and Jak2-STAT5 pathway These results suggest the pivotal role of lactic acid in physiological erythropoiesis
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