Notch-Expanded Murine Hematopoietic Stem and Progenitor Cells Mitigate Death from Lethal Radiation and Convey Immune Tolerance in Mismatched Recipients

Stem Cells Transl Med. 2017 Feb;6(2):566-575. doi: 10.5966/sctm.2016-0112. Epub 2016 Sep 13.


The hematopoietic syndrome of acute radiation syndrome (h-ARS) is characterized by severe bone marrow aplasia, resulting in a significant risk for bleeding, infections, and death. To date, clinical management of h-ARS is limited to supportive care dictated by the level of radiation exposure, with a high incidence of mortality in those exposed to high radiation doses. The ideal therapeutic agent would be an immediately available, easily distributable single-agent therapy capable of rapid in vivo hematopoietic reconstitution until recovery of autologous hematopoiesis occurs. Using a murine model of h-ARS, we herein demonstrate that infusion of ex vivo expanded murine hematopoietic stem and progenitor cells (HSPCs) into major histocompatibility complex mismatched recipient mice exposed to a lethal dose of ionizing radiation (IR) led to rapid myeloid recovery and improved survival. Survival benefit was significant in a dose-dependent manner even when infusion of the expanded cell therapy was delayed 3 days after lethal IR exposure. Most surviving mice (80%) demonstrated long-term in vivo persistence of donor T cells at low levels, and none had evidence of graft versus host disease. Furthermore, survival of donor-derived skin grafts was significantly prolonged in recipients rescued from h-ARS by infusion of the mismatched expanded cell product. These findings provide evidence that ex vivo expanded mismatched HSPCs can provide rapid, high-level hematopoietic reconstitution, mitigate IR-induced mortality, and convey donor-specific immune tolerance in a murine h-ARS model. Stem Cells Translational Medicine 2017;6:566-575.

Keywords: Hematopoietic-acute radiation syndrome; Mismatched mouse progenitor cells; Notch expansion; Skin grafts; Tolerance induction.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acute Radiation Syndrome / immunology
  • Acute Radiation Syndrome / metabolism
  • Acute Radiation Syndrome / therapy*
  • Animals
  • Cell Proliferation*
  • Cells, Cultured
  • Disease Models, Animal
  • Female
  • Graft Survival*
  • Hematopoiesis*
  • Hematopoietic Stem Cell Transplantation*
  • Hematopoietic Stem Cells / immunology
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / radiation effects*
  • Histocompatibility Antigens / immunology*
  • Histocompatibility*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Recovery of Function
  • Signal Transduction
  • Skin Transplantation*
  • Time Factors
  • Transplantation Tolerance*


  • Histocompatibility Antigens
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • delta protein