Stem cells in perinatal medicine

In response to the Thalidomide catastrophe which showed how vulnerable the human fetus is the Foundation for the Child with Handicap was founded in Bonn, Germany in 1967. The aim of the Foundation is the support, prevention, early recognition and therapy of children with handicap before and after birth dealing with issues such as alcohol in pregnancy, infections, prenatal diagnosis and therapy etc. and to foster scientific progress as well as the information of the public. For example the new possibilities of non-invasive prenatal testing (NIPT) were covered in a Symposium and a subsequent issue of this journal addressing scientific, medical, legal an ethical aspects (J. Perinat.Med. 2021, Volume 49, Issue 8).

Because of the progress in the area of stem cell research and therapy it was decided by the Foundation to update this important topic in a symposium which was held at the University Hospital Bonn on May 21, 2022.

Stem cells can renew themselves and differentiate into a range of specialized cell types, making them fascinating for research and medical care. There are generally three types of Stem cells, namely totipotent as well as embryonic Stem (ES) and non-ES pluripotent cells. The pluripotent nature of ES presents a significant potential in clinical applications, however ES therapies are still limited by biological, ethical, political and regulatory hurdles. A major breakthrough in the field was the detection and use of induced pluripotent cells (IPS) which can replace embryonal Stem cells for most applications [1]. Also placental mesenchymal Stem cells were found to be useful as graft for pre- and perinatal neurogeneration [2].

Non-ES stem cells can be found in several tissues, such as bone marrow (BM), skin, ovary, sperm, adipose tissue, and pregnancy products of umbilical cord blood (UCB), amniotic fluid, and placenta. The use of UCB-derived stem cells is expanding in the medical field [3], [4], [5] owing to the facts that UCB are easy to procure from waste products [6], [7], [8], [9] without risk to the donor, and the cells are “younger” than those obtained from adult BM and more tolerant to human leukocyte antigen (HLA) mismatches thus lowering the risk of graft-vs.-host disease (GVHD), where graft vs. leukemia reactions after bone marrow transplantation have been described [10]. Stem cells derived from UCB have been applied for therapy of malignant/nonmalignant diseases [7]. Allogeneic transplantations are performed between HLA-identical siblings and from HLA-matched unrelated donors [11]. Most recipients of cord blood are children with leukemia or genetic disorders, but also increasingly adolescents and adults, but the volume obtained from the umbilical cord often a disadvantage. Based on the promising results, cord blood banks with cryopreserved HLA-typed cord blood samples from anonymous donors are set up worldwide, ready to be used as allogeneic Stem cell graft [7, 9]. The enrichment of second and third trimester human fetal hematopoietic cord blood has been investigated but still proofs to be difficult [4].

Prenatal in utero Stem cell transplantation is a novel, promising therapeutic option for genetic disorders, which is now at the cutting edge of moving from preclinical research into clinical application [4]. Work on NOD/SCID mice has shown us that we achieved a marked difference in the engraftment rates between allogeneic (80% chimerim) and xenogeneic in utero transplantations. This challenges the dogma of immonologic inertia in utero. In the sheep model however we could obtain only a low level of engraftment, and in humans and we have systematically investigated how Stem cell applications in utero can be achieved technically using ultrasound guided intraperitoneal injections or endoscope prototypes which allow a good view in utero in the first trimester [6].

Strategies to improve the engraftment and reconstitution after in utero transplantation for early therapy, before extensive damage to various tissues and organs ensues, are currently investigated [12, 13] and this approach has been successful especially in cases of prenatally diagnosed X-linked severe combined immuno deficiency.

The first clinical experience shows that inborn diseases, such as X-linked severe combined immunodeficiency [7, 12], can be treated successfully in utero. Very limited therapeutic success has been achieved in genetic disorders which do not severely affect the immune system, and this failure is mostly due to immunologic rejection and hematopoietic competition between donor and host cells. Therefore, new strategies to improve the success are being developed, including e.g. graft modification, prenatal conditioning of the fetus, postnatal retransplan-tation after prenatal induction of immune tolerance and fetal gene therapy using autologous fetal Stem cells [12, 13].

In addition, so-called “private” cord blood banks have been set up mostly commercially, providing the possibility to store cord blood at birth from healthy children with no affected family member for a possible autologous Stem cell transplantation in the future, if the child later develops a disease such as leukemia. For several reasons, however, this procedure has been challenged scientifically as well as ethically. To date, there are no or very few established indication for an autologous cord blood transplantation [14].

The use of non-hematopoietic (e.g. mesenchymal) or pluripotent Stem cells will most probably lead to an expansion of the spectrum of indications in genetic diseases [15]. At the same time, ethical implications, in particular regarding fetal gene therapy, e.g. by gene editing and the use of pluripotent Stem cells must be addressed.

There is no doubt any more that there is a physiologie traffic of fetal material in every pregnancy from the fetal to the maternal side of the placenta, from intact cells over fetal debris to cell-free DNA, and this phenomenon can lead to chimerism in the mother even causing diseases such as scleroderma or thyreoiditis which look like an autoimmune disease but in fact are late consequences of an “allograft” [16].

In order to put the perinatal Stem cell research and development into perspective as a growing field of medicine the Symposium of the Foundation first covered the background of Stem cell programming for modulating disease and repair by Oliver Brüstle et al. who already in 2011 dealt with the “European Union’s Ruling on the Potentability of Human Embryonic Stem-Cell-Related Inventions” and has over time contributed significantly to the research in the field, e.g. their recent demonstration that small molecules enable highly efficient neuronal conversion of human fibroblasts.

Christoph Boesecke and his group covered the increasing clinical application of Stem cells in virology as well as oncology and Volker Busskamp and his group in treating retinal degeneration.

New uses of special cell types and technologies to perform therapy in premature babies for a wide spectrum of human diseases already in the perinatal period are currently investigated and covered in this special issue of JPM by Arne Jensen and his group.

Since perinatal brain damage is still a major contributor to fetal and neonatal mortality and morbidity this topic was covered by Brigitte Strizek and Mathias Wellmann and his group dealt with the question whether Stem cell therapy in neonates is already a valid option. The ethical and legal aspects of Stem cell therapy in perinatal medicine have always been a controversial topic covered elegantly by Klaus Gärditz in this issue.

Since Stem cells are pluripotent, a lot of hope was set into regenerative medicine approaches, and amazing progress has been made methodologically. Clinical results or breakthroughs, however, are only now emerging and especially in perinatal medicine some important trials are on the way. Therefore this research and development efforts have to be supported, critically evaluated and checked by clinical trials. The Foundation of the Child with Handicap tries to help with its Symposium and publication so that the public recognizes the most recent results but does not get false claims. Fiction needs to be differentiated from facts.