Suppression of Luteinizing Hormone Enhances HSC Recovery After Hematopoietic Injury

Nat Med. 2018 Feb;24(2):239-246. doi: 10.1038/nm.4470. Epub 2018 Jan 8.

Abstract

There is a substantial unmet clinical need for new strategies to protect the hematopoietic stem cell (HSC) pool and regenerate hematopoiesis after radiation injury from either cancer therapy or accidental exposure. Increasing evidence suggests that sex hormones, beyond their role in promoting sexual dimorphism, regulate HSC self-renewal, differentiation, and proliferation. We and others have previously reported that sex-steroid ablation promotes bone marrow (BM) lymphopoiesis and HSC recovery in aged and immunodepleted mice. Here we found that a luteinizing hormone (LH)-releasing hormone antagonist (LHRH-Ant), currently in wide clinical use for sex-steroid inhibition, promoted hematopoietic recovery and mouse survival when administered 24 h after an otherwise-lethal dose of total-body irradiation (L-TBI). Unexpectedly, this protective effect was independent of sex steroids and instead relied on suppression of LH levels. Human and mouse long-term self-renewing HSCs (LT-HSCs) expressed high levels of the LH/choriogonadotropin receptor (LHCGR) and expanded ex vivo when stimulated with LH. In contrast, the suppression of LH after L-TBI inhibited entry of HSCs into the cell cycle, thus promoting HSC quiescence and protecting the cells from exhaustion. These findings reveal a role of LH in regulating HSC function and offer a new therapeutic approach for hematopoietic regeneration after hematopoietic injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle / drug effects
  • Cell Cycle / radiation effects
  • Cell Differentiation / drug effects
  • Cell Differentiation / radiation effects
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Cell Proliferation / radiation effects
  • Cell Self Renewal / drug effects
  • Cell Self Renewal / genetics*
  • Cell Self Renewal / radiation effects
  • Gonadotropin-Releasing Hormone / antagonists & inhibitors
  • Hematopoiesis / drug effects
  • Hematopoiesis / genetics
  • Hematopoiesis / radiation effects
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism*
  • Hematopoietic Stem Cells / radiation effects
  • Humans
  • Luteinizing Hormone / metabolism*
  • Luteinizing Hormone / pharmacology
  • Mice
  • Radiation Injuries, Experimental / drug therapy*
  • Radiation Injuries, Experimental / metabolism
  • Radiation Injuries, Experimental / pathology
  • Receptors, LH / genetics
  • Regeneration / drug effects
  • Regeneration / genetics
  • Regeneration / radiation effects
  • Signal Transduction / drug effects
  • Signal Transduction / radiation effects
  • Whole-Body Irradiation

Substances

  • LHCGR protein, mouse
  • Receptors, LH
  • Gonadotropin-Releasing Hormone
  • Luteinizing Hormone