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A Step Towards the Treatment of Hematopoietic Disease with Amniotic Fluid Stem Cells

Review of “In Utero Transplantation of Expanded Autologous Amniotic Fluid Stem Cells Results in Long‐Term Hematopoietic Engraftment” from STEM CELLS by Stuart P. Atkinson

Previous research from the laboratory of Paolo De Coppi (UCL Great Ormond Street Institute of Child Health, London, UK) provided proof of principle for the hematopoietic potential of amniotic fluid stem cells (AFSCs) [1] and their multilineage hematopoietic engraftment following in utero transplantation [2]. Their overarching hope is to develop a strategy for the prenatal treatment of congenital hematological diseases with AFSCs sampled from the amniotic fluid; however, the loss of hematopoietic potential following in vitro expansion under adherent culture conditions in the presence of serum-containing media has tempered the therapeutic potential of AFSCs [3, 4] (See a review article from STEM CELLS here!).

Now, the De Coppi team returns with a STEM CELLS study that describes a means to in vitro expand HFSCs that engraft in a highly efficient manner following intravascular administration in a congenic (autologous-like) murine model of in utero transplantation [5]. The authors hope that their findings represent another step towards the use of autologous, in‐vitro expanded AFSCs as a therapeutic platform for the in utero treatment of inherited disorders of hematopoiesis.

Loukogeorgakis et al. first established that AFSCs (marked as c‐Kit+/Lin‐) displayed hematopoietic characteristics through detection of the expression of critical hematopoietic markers and hematopoietic regulators. Importantly, HFSCs retained said characteristics and their favorable proliferation kinetics during in vitro expansion on a feeder layer of mitotically inactivated mouse embryonic fibroblasts, which bodes well for their intended therapeutic applications in the treatment of inherited disorders of hematopoiesis. 

Encouragingly, the intravascular administration of a relatively small amount of autologous/congenic freshly isolated or cultured AFSCs supported higher levels of stable, long-term multilineage hematopoietic engraftment following in utero transplantation when compared to hematopoietic stem cells derived from the bone marrow. Indeed, all animals receiving AFSCs showed stable hematopoietic macrochimerism for up to six months, with engraftment in blood and bone marrow exceeding 20%. The authors also suggest that the intravascular administration, a superior approach to intraperitoneal delivery with more applicable translational characteristics, may contribute to the remarkable engraftment potential observed [6]. However, the authors reported the failure of in utero transplantation of allogenic AFSCs; the resultant adaptive immune response and donor cell rejection may be due to a lack of sufficient homing to the host fetal thymus and the subsequent lack of tolerance induction.

While this study highlights the ability of culture-expanded AFSCs to engraft following autologous/congenic in utero transplantation, which the authors hope will lead to the development of AFSC-based treatments for a range of inherited disorders of hematopoiesis, the authors anticipate the requirement for the induction of central tolerance for the success of allogenic hematopoietic engraftment. 

For more on the treatment of hematopoietic disease with human amniotic fluid stem cells, stay tuned to the Stem Cells Portal!

References

  1. Ditadi A, de Coppi P, Picone O, et al., Human and murine amniotic fluid c-Kit+Lin- cells display hematopoietic activity. Blood 2009;113:3953-60.
  2. Shangaris P, Loukogeorgakis SP, Blundell MP, et al., Long-Term Hematopoietic Engraftment of Congenic Amniotic Fluid Stem Cells After in Utero Intraperitoneal Transplantation to Immune Competent Mice. Stem Cells and Development 2018;27:515-523.
  3. De Coppi P, Bartsch G, Jr., Siddiqui MM, et al., Isolation of amniotic stem cell lines with potential for therapy. Nat Biotechnol 2007;25:100-6.
  4. Loukogeorgakis SP and De Coppi P, Concise Review: Amniotic Fluid Stem Cells: The Known, the Unknown, and Potential Regenerative Medicine Applications. Stem Cells 2017;35:1663-1673.
  5. Loukogeorgakis SP, Shangaris P, Bertin E, et al., In Utero Transplantation of Expanded Autologous Amniotic Fluid Stem Cells Results in Long-Term Hematopoietic Engraftment. STEM CELLS 2019;37:1176-1188.
  6. Boelig MM, Kim AG, Stratigis JD, et al., The Intravenous Route of Injection Optimizes Engraftment and Survival in the Murine Model of In Utero Hematopoietic Cell Transplantation. Biology of Blood and Marrow Transplantation 2016;22:991-999.