Current Stem Cell Reports

, Volume 4, Issue 1, pp 74–80 | Cite as

In Utero Hematopoietic Cell Transplantation: Past Clinical Experience and Future Clinical Trials

  • Russell G. Witt
  • Quoc-Hung L. Nguyen
  • Tippi C. MacKenzie
Prenatal Therapies (WH Peranteau, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Prenatal Therapies


Purpose of Review

In utero hematopoietic stem cell transplantation is an evolving therapy with possible implications for the treatment of many fetal disorders. Here, we present the past clinical experience and current clinical trials and discuss future directions for in utero therapy.

Recent Findings

Barriers to clinically meaningful in utero hematopoietic stem cell transplantation have been identified including maternal T cell-mediated graft rejection, achieving adequate space within the fetal bone marrow niche, and delivering adequate stem cells intravascularly. In a canine model of hematopoietic stem cell transplantation, high chimerism levels were achieved with maternal stem cells delivered intravascularly. Chimerism remained stable over a 2-year period without any evidence of graft-versus-host disease. Current clinical trials such as one for alpha thalassemia seek to apply these results in human diseases.


The field of in utero stem cell transplantation continues to improve and expand on the possible diseases that can be treated. The reasons for limited success in previous trials have been identified and current trials utilizing maternally derived stem cells at high doses are underway.


In utero hematopoietic stem cell transplantation Immune tolerance Fetal therapy Chimerism Stem cell niche 


Compliance with Ethical Standards

Conflict of Interest

Russell G. Witt, Quoc-Hung L. Nguyen, and Tippi C. MacKenzie declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Harrison MR, Golbus MS, Filly RA, Callen PW, Katz M, de Lorimier AA, et al. Fetal surgery for congenital hydronephrosis. N Engl J Med. 1982;306(10):591–3. Scholar
  2. 2.
    Van Kamp IL, Klumper FJ, Oepkes D, Meerman RH, Scherjon SA, Vandenbussche FP, et al. Complications of intrauterine intravascular transfusion for fetal anemia due to maternal red-cell alloimmunization. Am J Obstet Gynecol. 2005;192(1):171–7. Scholar
  3. 3.
    Johnson FL, Look AT, Gockerman J, Ruggiero MR, Dalla-Pozza L, Billings FT 3rd. Bone-marrow transplantation in a patient with sickle-cell anemia. N Engl J Med. 1984;311(12):780–3. Scholar
  4. 4.
    Kamani N, August CS, Douglas SD, Burkey E, Etzioni A, Lischner HW. Bone marrow transplantation in chronic granulomatous disease. J Pediatr. 1984;105(1):42–6. Scholar
  5. 5.
    Lucarelli G, Galimberti M, Polchi P, Angelucci E, Baronciani D, Giardini C, et al. Bone marrow transplantation in patients with thalassemia. N Engl J Med. 1990;322(7):417–21. Scholar
  6. 6.
    Parkman R. The application of bone marrow transplantation to the treatment of genetic diseases. Science. 1986;232(4756):1373–8. Scholar
  7. 7.
    Billingham RE, Brent L, Medawar PB. Actively acquired tolerance of foreign cells. Nature. 1953;172(4379):603–6.CrossRefPubMedGoogle Scholar
  8. 8.
    Touraine JL, Raudrant D, Royo C, Rebaud A, Roncarolo MG, Souillet G, et al. In-utero transplantation of stem cells in bare lymphocyte syndrome. Lancet. 1989;1(8651):1382.CrossRefPubMedGoogle Scholar
  9. 9.
    Flake AW, Roncarolo MG, Puck JM, Almeida-Porada G, Evans MI, Johnson MP, et al. Treatment of X-linked severe combined immunodeficiency by in utero transplantation of paternal bone marrow. N Engl J Med. 1996;335(24):1806–10. Scholar
  10. 10.
    Wengler GS, Lanfranchi A, Frusca T, Verardi R, Neva A, Brugnoni D, et al. In-utero transplantation of parental CD34 haematopoietic progenitor cells in a patient with X-linked severe combined immunodeficiency (SCIDXI). Lancet. 1996;348(9040):1484–7. Scholar
  11. 11.
    Owen RD. Immunogenetic consequences of vascular anastomoses between bovine twins. Science. 1945;102(2651):400–1. Scholar
  12. 12.
    Picus J, Holley K, Aldrich WR, Griffin JD, Letvin NL. A naturally occurring bone marrow-chimeric primate. II. Environment dictates restriction on cytolytic T lymphocyte-target cell interactions. J Exp Med. 1985;162(6):2035–52. Scholar
  13. 13.
    Griesemer AD, Sorenson EC, Hardy MA. The role of the thymus in tolerance. Transplantation. 2010;90(5):465–74. Scholar
  14. 14.
    Wing K, Sakaguchi S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol. 2010;11(1):7–13. Scholar
  15. 15.
    Caramalho I, Nunes-Cabaco H, Foxall RB, Sousa AE. Regulatory T-cell development in the human thymus. Front Immunol. 2015;6:395.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Fleischman RA, Mintz B. Prevention of genetic anemias in mice by microinjection of normal hematopoietic stem cells into the fetal placenta. Proc Natl Acad Sci U S A. 1979;76(11):5736–40. Scholar
  17. 17.
    Blazar BR, Taylor PA, Vallera DA. Adult bone marrow-derived pluripotent hematopoietic stem cells are engraftable when transferred in utero into moderately anemic fetal recipients. Blood. 1995;85(3):833–41.PubMedGoogle Scholar
  18. 18.
    Blazar BR, Taylor PA, Vallera DA. In utero transfer of adult bone marrow cells into recipients with severe combined immunodeficiency disorder yields lymphoid progeny with T- and B-cell functional capabilities. Blood. 1995;86(11):4353–66.PubMedGoogle Scholar
  19. 19.
    Pallavicini MG, Flake AW, Madden D, et al. Hematopoietic chimerism in rodents transplanted in utero with fetal human hematopoietic cells. Transplant Proc. 1992;24(2):542–3.PubMedGoogle Scholar
  20. 20.
    Nijagal A, Derderian C, Le T, Jarvis E, Nguyen L, Tang Q, et al. Direct and indirect antigen presentation lead to deletion of donor-specific T cells after in utero hematopoietic cell transplantation in mice. Blood. 2013;121(22):4595–602. Scholar
  21. 21.
    Peranteau WH, Hayashi S, Hsieh M, Shaaban AF, Flake AW. High-level allogeneic chimerism achieved by prenatal tolerance induction and postnatal nonmyeloablative bone marrow transplantation. Blood. 2002;100(6):2225–34. Scholar
  22. 22.
    Ashizuka S, Peranteau WH, Hayashi S, Flake AW. Busulfan-conditioned bone marrow transplantation results in high-level allogeneic chimerism in mice made tolerant by in utero hematopoietic cell transplantation. Exp Hematol. 2006;34(3):359–68. Scholar
  23. 23.
    Peranteau WH, Heaton TE, Gu YC, Volk SW, Bauer TR, Alcorn K, et al. Haploidentical in utero hematopoietic cell transplantation improves phenotype and can induce tolerance for postnatal same-donor transplants in the canine leukocyte adhesion deficiency model. Biol Blood Marrow Transplant. 2009;15(3):293–305. Scholar
  24. 24.
    Lee PW, Cina RA, Randolph MA, Arellano R, Goodrich J, Rowland H, et al. In utero bone marrow transplantation induces kidney allograft tolerance across a full major histocompatibility complex barrier in swine. Transplantation. 2005;79(9):1084–90. Scholar
  25. 25.
    • Peranteau WH, Hayashi S, Abdulmalik O, Chen Q, Merchant A, Asakura T, et al. Correction of murine hemoglobinopathies by prenatal tolerance induction and postnatal nonmyeloablative allogeneic BM transplants. Blood. 2015;126(10):1245–54. This paper underscored the therapeutic potential of establishing donor-specific tolerance, in which a “booster” stem cell transplant after in utero stem cell transplant led to improved engraftment as well as clinical amelioration in the mouse models of β-thalassemia and sickle cell disease. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Flake AW, Zanjani ED. In utero hematopoietic stem cell transplantation: ontogenic opportunities and biologic barriers. Blood. 1999;94(7):2179–91.PubMedGoogle Scholar
  27. 27.
    Peranteau WH, Endo M, Adibe OO, Flake AW. Evidence for an immune barrier after in utero hematopoietic-cell transplantation. Blood. 2007;109(3):1331–3.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Merianos DJ, Tiblad E, Santore MT, Todorow CA, Laje P, Endo M, et al. Maternal alloantibodies induce a postnatal immune response that limits engraftment following in utero hematopoietic cell transplantation in mice. J Clin Invest. 2009;119(9):2590–600. Scholar
  29. 29.
    •• Nijagal A, Wegorzewska M, Jarvis E, Le T, Tang Q, MacKenzie TC. Maternal T cells limit engraftment after in utero hematopoietic cell transplantation in mice. J Clin Invest. 2011;121(2):582–92. This manuscript defined a cellular mechanism for maternal T cell-mediated rejection of third party cells in mice and provides a rationale for performing maternal stem cell transplants in clinicl trials. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Mold JE, Michaelsson J, Burt TD, Muench MO, Beckerman KP, Busch MP, et al. Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. Science. 2008;322(5907):1562–5. Scholar
  31. 31.
    Alhajjat AM, Durkin ET, Shaaban AF. Regulation of the earliest immune response to in utero hematopoietic cellular transplantation. Chimerism. 2010;1(2):61–3. Scholar
  32. 32.
    Alhajjat AM, Lee AE, Strong BS, Shaaban AF. NK cell tolerance as the final endorsement of prenatal tolerance after in utero hematopoietic cellular transplantation. Front Pharmacol. 2015;6:51.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    •• Vrecenak JD, Pearson EG, Santore MT, Todorow CA, Li H, Radu A, et al. Stable long-term mixed chimerism achieved in a canine model of allogeneic in utero hematopoietic cell transplantation. Blood. 2014;124(12):1987–95. This is an important pre-clinical study showing that transplantation of a high dose of maternal-derived HSCs leads to clinically relevant levels of engraftment and donor-specific tolerance in a large animal model. Google Scholar
  34. 34.
    MacKenzie TC, David AL, Flake AW, Almeida-Porada G. Consensus statement from the first international conference for in utero stem cell transplantation and gene therapy. Front Pharmacol. 2015;6:15.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    IFeTIS. International Fetal Transplantation and Immunology Society 2016 Available from:
  36. 36.
    TC M. In Utero Hematopoietic Stem Cell Transplantation for Alpha-thalassemia Major (ATM) 2017 Available from:
  37. 37.
    Derderian SC, Jeanty C, Walters MC, Vichinsky E, MacKenzie TC. In utero hematopoietic cell transplantation for hemoglobinopathies. Front Pharmacol. 2014;5:278.PubMedGoogle Scholar
  38. 38.
    Kreger EM, Singer ST, Witt RG, Sweeters N, Lianoglou B, Lal A, et al. Favorable outcomes after in utero transfusion in fetuses with alpha thalassemia major: a case series and review of the literature. Prenat Diagn. 2016;36(13):1242–9. Scholar
  39. 39.
    Gotherstrom C, et al. Stem cells and fetal therapy: is it a reality? Obstet, Gynaecol Reprod Med. 2017;27(5):166–7. Scholar
  40. 40.
    Gotherstrom C, Westgren M, Shaw SW, Astrom E, Biswas A, Byers PH, et al. Pre- and postnatal transplantation of fetal mesenchymal stem cells in osteogenesis imperfecta: a two-center experience. Stem Cells Transl Med. 2014;3(2):255–64. Scholar
  41. 41.
    Chervenak FA, McCullough LB. The ethics of maternal-fetal surgery. Semin Fetal Neonatal Med. 2017;
  42. 42.
    Harrison DE, Zhong RK, Jordan CT, Lemischka IR, Astle CM. Relative to adult marrow, fetal liver repopulates nearly five times more effectively long-term than short-term. Exp Hematol. 1997;25(4):293–7.PubMedGoogle Scholar
  43. 43.
    Rosler ES, Brandt JE, Chute J, Hoffman R. An in vivo competitive repopulation assay for various sources of human hematopoietic stem cells. Blood. 2000;96(10):3414–21.PubMedGoogle Scholar
  44. 44.
    Czechowicz A, Kraft D, Weissman IL, Bhattacharya D. Efficient transplantation via antibody-based clearance of hematopoietic stem cell niches. Science. 2007;318(5854):1296–9. Scholar
  45. 45.
    McGovern PE, Czechowicz A, Mejaddam A, Stratigis JD, Li H, Urwin J, et al. Enhanced allogeneic engraftment achieved via prenatal tolerance induction and postnatal anti-CD45 immunotoxin conditioned hematopoietic cell transplantation. Blood. 2016;128(22):2153.Google Scholar
  46. 46.
    • Derderian SC, Togarrati PP, King C, Moradi PW, Reynaud D, Czechowicz A, et al. In utero depletion of fetal hematopoietic stem cells improves engraftment after neonatal transplantation in mice. Blood. 2014;124(6):973–80. This paper shows that in utero depletion of the stem cell niche with anti-c-kit antibody leads to improved engraftment of neonatally transplanted stem cells. This supports earlier evidence that the endogenous fetal stem cell niche may provide a competitive disadvantage to transplanted stem cells. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Mokhtari S, Colletti EJ, Atala A, Zanjani ED, Porada CD, Almeida-Porada G. Boosting hematopoietic engraftment after in utero transplantation through vascular niche manipulation. Stem Cell Repo. 2016;6(6):957–69. Scholar
  48. 48.
    Huang Y, Bozulic LD, Miller T, Xu H, Hussain LR, Ildstad ST. CD8α+ plasmacytoid precursor DCs induce antigen-specific regulatory T cells that enhance HSC engraftment in vivo. Blood. 2011;117(8):2494–505. Scholar
  49. 49.
    Shaaban AF, Kim HB, Gaur L, Liechty KW, Flake AW. Prenatal transplantation of cytokine-stimulated marrow improves early chimerism in a resistant strain combination but results in poor long-term engraftment. Exp Hematol. 2006;34(9):1278–87. Scholar
  50. 50.
    Peranteau WH, Endo M, Adibe OO, Merchant A, Zoltick PW, Flake AW. CD26 inhibition enhances allogeneic donor-cell homing and engraftment after in utero hematopoietic-cell transplantation. Blood. 2006;108(13):4268–74. Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Russell G. Witt
    • 1
    • 2
  • Quoc-Hung L. Nguyen
    • 1
    • 2
  • Tippi C. MacKenzie
    • 1
    • 2
  1. 1.The Center for Maternal-Fetal Precision MedicineUniversity of CaliforniaSan FranciscoUSA
  2. 2.The Department of SurgeryUniversity of CaliforniaSan FranciscoUSA

Personalised recommendations