Neocytolysis: Quantification, characterization, and mechanisms of the destruction of newly formed erythrocytes upon return from high altitude

• Applicants: Professor Dr. Lars Kaestner; Professor Dr. Heimo Mairbäurl
• Subject Area: Hematology, Oncology ; Anatomy and Physiology
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 402842496

• Final Report Year: 2022

Final Report Abstract

Our results confirm the increase in total Hb-mass during the stay at high altitude, and show a rapid decrease towards pre-altitude values after return to low altitude. However, the pattern of changes of the age-cohort label of erythrocytes that had been produced at high altitude was not different from that of low altitude erythrocytes indicating normal survival of altitude-produced erythrocytes. This indicates that there was no selective destruction of the erythrocytes produced at high altitude, which the concept of neocytolysis had predicted. This disprove of the concept is supported by the low levels of band 4.1a/b ratio after descent, which also indicates that these young cells are still present in circulating blood. Modelling based on the changes of CD71-positive reticulocyte numbers indicates that a transient reduction in the rate of erythropoiesis by approximately 35% is sufficient to explain the decrease in tot-Hb within 10 days after ascent. Therefore, the reduction in total Hb-mass is likely, and most intuitively, a consequence of reduced erythrocyte production rates upon descent. The results of the in vitro erythropoiesis highlight an accelerated erythroid maturation at low oxygen and more concave morphology of reticulocytes. No differences in deformability were observed in the formed reticulocytes in the tested conditions. Moreover, hematopoietic stem and progenitor cells isolated from blood affected by hypoxia at high altitude did not result in different erythroid development, suggesting no retention of a high-altitude signature but rather an immediate adaptation to oxygen concentration. This adaptation was observed during in vitro erythropoiesis at three percent oxygen by a significantly increased glycolytic metabolic profile. These hypoxia-induced effects on in vitro erythropoiesis fail to provide an intrinsic explanation of the concept of neocytolysis. Therefore, a process like "neocytolysis" could not be detected and therefore most likely does not contribute to the decrease in tot-Hb after descent from a stay at high altitude.

Publications

• (2021). "Absence of neocytolysis in humans returning from a 3-week high-altitude sojourn." Acta Physiol (Oxf): e13647
  Klein, M., L. Kaestner, A. Y. Bogdanova, G. Minetti, S. Rudloff, C. Lundby, A. Makhro, E. Seiler, A. van Cromvoirt, S. Fenk, G. Simionato, L. Hertz, S. Recktenwald, L. Schafer, T. Haider, S. Fried, C. Borsch, H. H. Marti, A. Sander and H. Mairbäurl
  
• (2021). "Of mice and men (1) : how to achieve a better life with lower total Hb mass after returning from hypoxia to normoxia." Acta Physiol (Oxf): e13720
  Mairbäurl, H., L. Kaestner, A. Yu Bogdanova, M. Klein and G. Minetti
  
• (2021). "So is science ..."(1) : No evidence for neocytolysis on descending the mountains (Response to Rice and Gunga)." Acta Physiol (Oxf): e13709
  Recktenwald, S. M., L. Kaestner, A. Y. Bogdanova, G. Minetti, M. Klein and H. Mairbäurl
  
• (2022). "In vitro erythropoiesis at different pO2 induces adaptations that are independent of prior systemic exposure to hypoxia." Cells Tissues Organs 11: 1082
  Simionato, G., A. Rabe, J. S. Gallego-Murillo, C. van der Zwaan, A. J. Hoogendijk, M. van den Biggelaar, G. Minetti, A. Bogdanova, H. Mairbäurl, C. Wagner, L. Kaestner and E. van den Akker