Novel strategy for successful long-term hematopoietic recovery after transplanting a limited number of hematopoietic stem/progenitor cells

Hakmo Lee, Ho Seon Park, Ok Kyung Choi, Ju Eun Oh, Sung Soo Chung, Hye Seung Jung, Kyong Soo Park

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Various investigators have attempted to overcome the shortage of available hematopoietic stem/progenitor cells (HSPCs) by facilitating their engraftment after transplantation. Preconditioning of HSPCs with the granulocyte-derived cationic peptide LL-37 has been suggested as a useful strategy to facilitate engraftment of transplanted cells by enhancing their responsiveness to CXCL12. In this study, we evaluated whether LL-37 preconditioning is acceptable for clinical application. We found that the effect of LL-37 preconditioning was specific to clonogenic cells and was mediated specifically by increased calcium influx with the activation of downstream signaling through mammalian target of rapamycin complex 1 (mTORC1). Because hyperactivation of mTORC1 and the disruption of 5' adenosine monophosphate-activated protein kinase (AMPK) are known to deplete HSPC pools, we compared the repopulation capacity of HSPCs preconditioned with LL-37 and those preconditioned with AMPK activator (AICAR). Invivo competitive repopulation experiments revealed that LL-37 preconditioning impairs long-term repopulation of transplanted HSPCs, suggesting that this strategy might not acceptable for clinical applications in which long-term repopulation capacity is a prerequisite. AICAR preconditioning dramatically enhanced the long-term repopulation of transplanted HSPCs, however. Taken together, these results suggest that future strategies to ensure successful transplantation outcomes should focus on protecting HSPCs from various stimuli during their homing to the bone marrow niches rather than activating them before transplantation.

Original languageEnglish
Pages (from-to)1282-1289
Number of pages8
JournalBiology of Blood and Marrow Transplantation
Volume20
Issue number9
DOIs
StatePublished - 1 Jan 2014

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Hematopoietic Stem Cells
Transplantation
Adenosine Monophosphate
Protein Kinases
Granulocytes
Bone Marrow
Research Personnel

Keywords

  • AMPK
  • Hematopoietic stem cell
  • LL-37
  • MTORC1
  • Transplantation

Cite this

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abstract = "Various investigators have attempted to overcome the shortage of available hematopoietic stem/progenitor cells (HSPCs) by facilitating their engraftment after transplantation. Preconditioning of HSPCs with the granulocyte-derived cationic peptide LL-37 has been suggested as a useful strategy to facilitate engraftment of transplanted cells by enhancing their responsiveness to CXCL12. In this study, we evaluated whether LL-37 preconditioning is acceptable for clinical application. We found that the effect of LL-37 preconditioning was specific to clonogenic cells and was mediated specifically by increased calcium influx with the activation of downstream signaling through mammalian target of rapamycin complex 1 (mTORC1). Because hyperactivation of mTORC1 and the disruption of 5' adenosine monophosphate-activated protein kinase (AMPK) are known to deplete HSPC pools, we compared the repopulation capacity of HSPCs preconditioned with LL-37 and those preconditioned with AMPK activator (AICAR). Invivo competitive repopulation experiments revealed that LL-37 preconditioning impairs long-term repopulation of transplanted HSPCs, suggesting that this strategy might not acceptable for clinical applications in which long-term repopulation capacity is a prerequisite. AICAR preconditioning dramatically enhanced the long-term repopulation of transplanted HSPCs, however. Taken together, these results suggest that future strategies to ensure successful transplantation outcomes should focus on protecting HSPCs from various stimuli during their homing to the bone marrow niches rather than activating them before transplantation.",
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Novel strategy for successful long-term hematopoietic recovery after transplanting a limited number of hematopoietic stem/progenitor cells. / Lee, Hakmo; Park, Ho Seon; Choi, Ok Kyung; Oh, Ju Eun; Chung, Sung Soo; Jung, Hye Seung; Park, Kyong Soo.

In: Biology of Blood and Marrow Transplantation, Vol. 20, No. 9, 01.01.2014, p. 1282-1289.

Research output: Contribution to journalArticle

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T1 - Novel strategy for successful long-term hematopoietic recovery after transplanting a limited number of hematopoietic stem/progenitor cells

AU - Lee, Hakmo

AU - Park, Ho Seon

AU - Choi, Ok Kyung

AU - Oh, Ju Eun

AU - Chung, Sung Soo

AU - Jung, Hye Seung

AU - Park, Kyong Soo

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