Temporal definition of haematopoietic stem cell niches in a large animal model of in utero stem cell transplantation

Authors

  • Christine Jeanblanc,

    1. Department of Agriculture, Nutrition and Veterinary Sciences, University of Nevada, Reno, NV, USA
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  • Angelina Daisy Goodrich,

    1. Department of Agriculture, Nutrition and Veterinary Sciences, University of Nevada, Reno, NV, USA
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  • Evan Colletti,

    1. Department of Agriculture, Nutrition and Veterinary Sciences, University of Nevada, Reno, NV, USA
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  • Saloomeh Mokhtari,

    1. Wake Forest Institute for Regenerative Medicine, Wake Forest University, Winston-Salem, NC, USA
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  • Christopher D. Porada,

    1. Wake Forest Institute for Regenerative Medicine, Wake Forest University, Winston-Salem, NC, USA
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  • Esmail D. Zanjani,

    Corresponding author
    1. Department of Agriculture, Nutrition and Veterinary Sciences, University of Nevada, Reno, NV, USA
    • Correspondence: Professor Graça Almeida-Porada, MD, PhD, Wake Forest Institute for Regenerative Medicine, Wake Forest University, Winston-Salem, NC 27157, USA.

      E-mail: galmeida@wakehealth.edu

      and

      Professor Esmail D. Zanjani, PhD, Department of Agriculture, Nutrition and Veterinary Sciences, University of Nevada, Reno, 1664 North Virginia Street, Reno, NV 89557, USA.

      E-mail: ezanjani@cabnr.unr.edu

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  • Graça Almeida-Porada

    Corresponding author
    1. Wake Forest Institute for Regenerative Medicine, Wake Forest University, Winston-Salem, NC, USA
    • Correspondence: Professor Graça Almeida-Porada, MD, PhD, Wake Forest Institute for Regenerative Medicine, Wake Forest University, Winston-Salem, NC 27157, USA.

      E-mail: galmeida@wakehealth.edu

      and

      Professor Esmail D. Zanjani, PhD, Department of Agriculture, Nutrition and Veterinary Sciences, University of Nevada, Reno, 1664 North Virginia Street, Reno, NV 89557, USA.

      E-mail: ezanjani@cabnr.unr.edu

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Summary

The fetal sheep model has served as a biologically relevant and translational model to study in utero haematopoietic stem cell transplantation (IUHSCT), yet little is known about the ontogeny of the bone marrow (BM) niches in this model. Because the BMmicroenvironment plays a critical role in the outcome of haematopoietic engraftment, we have established the correlation between the fetal-sheep and fetal-human BM niche ontogeny, so that studies addressing the role of niche development at the time of IUHSCT could be accurately performed. Immunofluorescence confocal microscopic analysis of sheep fetal bone from gestational days (gd) 25–68 showed that the BM microenvironment commences development with formation of the vascular niche between 25 and 36 gd in sheep; correlating with the events at 10–11 gestational weeks (gw) in humans. Subsequently, between 45 and 51 gd in sheep (c. 14 gw in humans), the osteoblastic/endosteal niche started developing, the presence of CD34+ CD45+ cells were promptly detected, and their number increased with gestational age. IUHSCT, performed in sheep at 45 and 65 gd, showed significant haematopoietic engraftment only at the later time point, indicating that a fully functional BM microenvironment improved engraftment. These studies show that sheep niche ontogeny closely parallels human, validating this model for investigating niche influence/manipulation in IUHSCT engraftment.

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