Prenatal stem cell therapy is predicated on two chief premises: enhanced outcome from intervention performed as early as possible and the unparalleled patterns of cell kinetics and tolerance of the fetus as a host. It has experienced exponential, mostly experimental development over the last 40 years, with clinical applications having been reported for a variety and ever expanding list of diseases, at different anecdotal or formal trial phase levels, since the late 1980’s1, 2, 3. Results have been inconsistent at best, which is typical of a field still in its infancy, but such inconsistency coexists with a defensible optimism based on notable experimental data and fascinating biological insights involving assorted stem cell phenotypes and effects, with or without targeted gene manipulations. Also expected of a new field are the still nascent initiatives for international collaboration and standardization3. Nevertheless, enough and diverse knowledge has already been produced so that even complete textbooks have been written on the subject, by various authors, and continue to multiply4.

It is beyond the scope of this review to summarize the whole burgeoning field of intrauterine cell therapy. Rather, we will focus on an emerging variant of it, coined transamniotic stem cell therapy (TRASCET), which offers the least invasive means to date of delivering cells to virtually any anatomical site in the fetus. It was first reported experimentally only less than a decade ago, thus, expectedly, it has yet to be attempted clinically5, 6, 7, 8. Yet, its biological basis, practicality, animal data, ethical validation, potential impact, and current status of national and international efforts to approve a first clinical application all justify this summarized overview.

The idea that the amniotic fluid could constitute a medium for mammalian fetal stem cell therapy stemmed directly from the first description of a biological role for an amniotic fluid cell, which happened to involve amniotic fluid-derived mesenchymal stem cells (afMSCs). Until that work, amniotic fluid cells, regardless of phenotype or progenitor status, were thought to be merely shed into the amniotic fluid at the end of their life cycle, with their presence in that medium being mistakenly interpreted as no more than a byproduct of other biological processes. However, in consecutive experiments in fetal lambs combined into a single report, it has been shown that afMSCs actually contribute to fetal tissue repair9. The fact that afMSCs are present in the fluid throughout gestation may be for that very reason. In retrospect, this finding was actually consistent with the long known role of MSCs from other sources, most notably bone marrow, in promoting postnatal tissue repair at numerous anatomical sites and in a plethora of clinical settings10, 11, 12. This is why the first and still most studies on TRASCET involve MSCs, which can be derived from different sources besides the amniotic fluid. From a translational perspective, afMSCs are arguably more applicable in a TRASCET setting than MSCs from any other source, not only because they are being used in their native environment, but also due to the fact that they can be autologous cells procured from minute samples obtained by one of the least invasive of whole fetal cell procurement methods, a plain amniocentesis, which sometimes may even already be indicated for select diagnostic purposes in a mother carrying a fetus with a congenital anomaly. Nonetheless, fetal MSCs from other sources, such as the placenta, are also an option and in fact have been used for TRASCET experimentally (details below). Despite the expected preponderance of studies on TRASCET based on MSCs, TRASCET has been proven viable experimentally utilizing at least three different phenotypes of donor cells so far: MSCs, hematopoietic stem cells (HSCs), and neural stem cells (NSCs)13.