Erythropoietin modulation is associated with improved homing and engraftment after umbilical cord blood transplantation

Omar S. Aljitawi, Soumen Paul, Avishek Ganguly, Tara L. Lin, Sid Ganguly, George Vielhauer, Maegan L. Capitano, Amy Cantilena, Brea Lipe, Jonathan D. Mahnken, Amanda Wise, Abigale Berry, Anurag K. Singh, Leyla Shune, Christopher Lominska, Sunil Abhyankar, Dennis Allin, Mary Laughlin, Joseph P. McGuirk and Hal E. Broxmeyer

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  • RE:The relevance of oxygen gradient and vascular polarization of the BM-niche for improving CD34+ stem cell engraftment
    • Omar S. Aljitawi, BMT Specialist University of Rochester Medical Center
    • Other Contributors:
      • Soumen Paul, Associate Professor Dept. of Pathology and Laboratory Medicine

    In their recently published paper, Perucca et al provide an evidence of modulation of VEGF gene in mesenchymal stem cells (MSCs) when co-cultured with umbilical cord blood (UCB) CD34+ cells.1 Under their culture conditions, UCB CD34+ cells preferentially underwent erythroid differentiation evident by an increase in BFU-E. In their letter to the editor, Perucca et al speculate that MSCs co-cultured with UCB CD34+ cells could polarize the bone marrow towards a vascular niche as VEGF among other genes modulated in MSCs in their culture system represent molecular pathways that involve hypoxia and angiogenesis. Our recently published findings link the reduction of erythropoietin (EPO) in the host, induced by hyperbaric oxygen (HBO), to improved UCB CD34+ cell transmigration toward SDF-1 and to improved UCB in vivo homing and engraftment.2 Perucca et al speculate that under low EPO conditions induced by HBO, the interaction of MSCs with UCB CD34+ cells in the bone marrow could result in an initial enhancement of erythroid differentiation related to initial UCB CD34+ cell contact with MSCs followed by subsequent enhancement of myeloid and megakaryocytic differentiation in response to activation of hypoxia-related genes, like VEGF, in the MSCs.

    Our published data showed that low EPO environment induced by HBO conditions resulted in reduced erythroid differentiation and enhanced myeloid differentiation. Interestingly, time to transfusion independency for red blood cells, wa...

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    Conflict of Interest:
    None declared.
  • RE: The relevance of oxygen gradient and vascular polarization of the BM-niche for improving CD34+ stem cell engraftment
    • Simone Perucca, Researcher Unit of Blood Diseases and Stem Cells Transplantation, Department of Clinical and Experimental Sciences, University of Brescia
    • Other Contributors:
      • Michele Malagola, Researcher and Physician
      • Simona Bernardi, Researcher
      • Domenico Russo, Full Professor and Head of Chair of Hematology

    To the Editor:

    In this paper, Aljitawi et al. demonstrated that systemic reduction of serum erythropoietin (EPO) levels in the host or blocking EPO-EPO receptor(R) signaling could be an effective strategy to improve bone marrow (BM) homing and engraftment of umbilical cord-blood hematopoietic stem cells (UCB-CD34+) after allogeneic umbilical cord-blood transplantation (UCBT).
    Through an “in vitro” co-culture system, we found that the human BM-derived mesenchymal stromal cell (MSCs) induce a significant increase of UCB-CD34+ cell number (fold increase=14.68; P<0,01) and a preferential differentiation towards the erythroid lineage. By gene set enrichment analysis, a significant enrichment in genes involved in heme metabolism (LAMP2, CLCN3, BMP2K) and in oxygen-level response (TNFAIP3, SLC2A3, KLF6) and angiogenesis (e.g. VEGFA, IGF1, ID1) was observed in UCB-CD34+ cells and in MSCs, respectively [1].
    Overall, our results suggest that MSCs can exert a priming effect on UCB-CD34+ stem cells, regulating their proliferation and erythroid differentiation, at least in the early phase after transplantation. In turn, UCB-CD34+ stem cells seem to be able to polarize the BM-niche towards the vascular compartment by modulating molecular pathways related to hypoxia and angiogenesis.
    Our observations appears to be concordant with the ones published by Aljitawi et al. and support the hypothesis that O2/EPO axis, a vascular polarization of BM-niche, and the ear...

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    Conflict of Interest:
    None declared.