The thermal response and development of thermotolerance of the bone marrow stromal progenitor CFU-F.

The effect of hyperthermia on the murine bone marrow stromal progenitor (fibroblast colony-forming unit, CFU-F) was evaluated and its ability to develop thermotolerance demonstrated. CFU-F were obtained from nucleated marrow of Balb/c mice and heated in vitro in alpha minimum essential medium plus 15% fetal bovine serum. Thermotolerance development was tested two ways. 1) The development of thermotolerance during prolonged hyperthermia was observed with a "step-up" heating protocol (i.e., cells were incubated at 41 degrees C and at regular intervals challenged with 15 min at 44 degrees C). 2) The development of thermotolerance at 37 degrees C after a short exposure to a high temperature (greater than or equal to 43 degrees C) was observed with a split treatment protocol that consisted of two 15-min treatments of 44 degrees C separated with time at 37 degrees C. The inverse of the slopes of the hyperthermia dose-response relationships (Do +/- SE) for CFU-F were 118 +/- 14, 53 +/- 7, 23 +/- 0.6, 11 +/- 0.3, 7 +/- 0.3, and 5 +/- 0.5 min for exposures of 41.5 degrees, 42 degrees, 42.5 degrees, 43 degrees, 43.5 degrees, and 44 degrees C, respectively. The plot of the slopes of the heat "dose-response" relationships versus the inverse of the absolute temperature (Arrhenius plot) yields a change in slope at approximately 43 degrees C, and the inactivation enthalpies (slopes above and below the inflection point at 43 degrees C) were 606 +/- 100 kJ/mol (145 +/- 24 kcal/mol) and 1372 +/- 29 kJ/mol (328 +/- 7 kcal/mol) above and below 43 degrees C, respectively. The maximum thermotolerance ratio (TTR, surviving fraction after maximum thermotolerance development to surviving fraction of normotolerant CFU-F) at 37 degrees C after an acute thermal exposure to 15 min at 44 degrees C occurred after 12 h, with a half time of 60 min and a TTR of 41. The maximum TTR during prolonged hyperthermia at 41 degrees C was 2.4 by approximately 50 min. These results show that CFU-F are as sensitive as committed hematopoietic precursors (e.g., granulocyte-macrophage colony-forming units, CFU-GM) to hyperthermia over a wide range of thermal exposures and are capable of thermotolerance development during prolonged hyperthermic exposures and at 37 degrees C after short exposures. We conclude that at least one of the stromal elements of normal marrow may be compromised during whole-body or regional clinical hyperthermia protocols.