Stem Cell Therapies in Obstetrics and

Gynaecology: The Female Urogenital

Tract and the Fetus as Sources and Targets
for Molecular and Regenerative Medicine
Scientific Impact Paper No. 38
May 2013
Stem Cell Therapies in Obstetrics and Gynaecology:
The Female Urogenital Tract and the Fetus as Sources and
Targets for Molecular and Regenerative Medicine
This is the first edition of this paper.

1. Introduction
Reproductive tissues are now recognised as sources of stem/progenitor cells and as targets for
regenerative medicine. This paper briefly reviews the progress and future challenges of applying
regenerative medicine to the urogenital tract and the use of stem cells for the treatment of inherited
genetic diseases, especially those with irreversible perinatal damage. Stem cells sourced from
reproductive tissues have been used or investigated for their potential use in other areas such as
haematological disease, traditionally treated with haematopoietic stem cells (HSC) from adult sources
but for which toxic adjuvant treatments, or bone tissue engineering, are concurrently needed.1 However,
applications of such methods, together with the use of stem cells for gamete generation, are beyond the
scope of this paper.
Briefly, stem cells have two properties. The first is the ability to self–renew or undertake numerous cell
divisions, while maintaining an undifferentiated state. The second is that of multipotency; the capacity
to differentiate into a mature cell type. Totipotent stem cells, from the morula, can differentiate into
embryonic and extraembryonic cell types, and can produce a complete and viable organism. Pluripotent
stem cells descend from totipotent cells and differentiate into tissues derived from any of the three germ
layers, including fetal tissues (amniotic fluid cells, the amnion, umbilical cord and placenta). Embryonic
stem cells are pluripotent, having been derived from the inner cell mass of a blastocyst. Multipotent stem
cells differentiate into various tissues originating from a single germ layer, for example, mesenchymal or
haemopoietic stem cells. Unipotent cells such as muscle satellite cells on the other hand, produce only
their own cell type but show greater self–renewal than fully mature cells. Theoretically, the more
primitive or “potent” a stem cell is, the more predisposed it is to uncontrolled cell division, and the
greater its potential for oncogenesis. Although there is some concern regarding the oncogenic potential
of pluripotent stem cells such as embryonic stem cells and induced pluripotent stem cells, nonpluripotent
cell sources are not inherently oncogenic.
Embryonic stem (ES) cells offer the prospect of novel treatments in regenerative medicine although
progress here has been impeded by controversies surrounding the source. However, multipotent cells are
now being isolated from several fetal tissues, readily obtained as products of diagnostic tests, at
disruption of pregnancy and at birth. In the field of gynaecology, regenerative medicine approaches to
repair or replace damaged or diseased urogenital tract organs, such as the urinary sphincter, pelvic floor,
uterus, ovaries and vagina, are currently in the preclinical and clinical phases of study. In obstetrics, the
area of stem cell transplantation has been largely focused on fetal therapy.

2. Stem cells from reproductive tissues

Over the past decade, stem cells have been isolated from embryonic, fetal and extra–fetal tissues, as well
as adult gonads. Extra–fetal tissues such as the amniotic membranes and placenta share a common
origin; the inner cell mass of the blastocyst, which gives rise to the embryo, yolk sac, mesenchymal core
of the chorionic villi, chorion and amnion. Most likely because of their shared origin, amniotic fluid and
the placenta contain a heterogeneous population of progenitor cells. This includes mesenchymal,
hematopoietic, trophoblastic and, perhaps, more primitive stem cells. Although the chemical and cellular
composition of the amniotic fluid varies with gestational age and fetal health status, mesenchymal stem
cells (MSC) can be consistently isolated at any gestation. Placental and amniotic fluid MSC have been

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shown to differentiate into most cell types of mesodermal lineage, as well as into a few cells of
ectodermal and endodermal lineages.2 The full spectrum of differentiation remains to be defined in its
entirety. Additional cell types have been isolated from amniotic fluid, including a population of CD–117
positive cells which express markers of pluripotentiality, demonstrate self–renewal through more than
50 population doublings while maintaining telomere length, are nontumourigenic and can differentiate
into tissues of all three germ layers.3 Their ability to be used for autologous and allogeneic cell sources
for regenerative medicine applications are currently being explored but will require a facility dedicated
to their characterisation, immunogenicity properties and storage.
Fetal stem cells have been isolated from various parts of the fetus. Early gestation HSC from the bone
marrow and liver are well characterised,4 with placental HSC being described more recently.5 Primitive
human fetal MSC (hfMSC) have been isolated from virtually every part of the developing fetus,6 have
higher proliferative capacity,7 express significant higher amounts of telomerase and have longer
telomeres8 compared to their adult counterparts. Additionally, they differentiate efficiently into neuronal
and muscle lineages and have shown more robust differentiation down the osteogenic lineage than the
later perinatal and adult sources of MSC,9 suggesting their utility for postnatal applications for bone
tissue engineering.1 Primitive hfMSC are readily transduced by integrating vectors and do not express
HLA–II or costimulatory molecules CD80 and CD86,10 indicating their utility for ex vivo gene therapy
and allogeneic use.11

3. Sample collection and stem cell banking

The use of fetal and perinatal stem cells in regenerative medicine should be regulated through
appropriate institutional and regulatory boards. Protocols for optimal collection of such tissues should
maximise the quantity and quality of stem cells derived prior to their banking within Good
Manufacturing Practice (GMP) facilities. The banking of umbilical cord blood (UCB) is an established
process in many centres worldwide, is a source of HSC12 and MSC13 and has established utility for
allogeneic postnatal treatment of haematological diseases such as leukaemia and bone marrow failure.14
Although there is a trend towards nondirected autologous banking of UCB in low risk families
promulgated largely by private cord blood banks, this practice has not been supported by several
academic institutions.15,16 However, there may be an advantage to private banking for directed use in a
family with a sibling affected by a medical condition that can potentially benefit from UCB.17
Harvesting of stem cells from fetal tissue following medically indicated pregnancy termination should be
guided by the specific cell targeted, if the harvested cells are intended for a particular application. hfMSC
have been collected from the liver for intrauterine transplantation targeting osteogenesis imperfecta and
for the treatment of haemoglobinopathies, both of which should be processed in GMP conditions.19
However, as a source for donor cells, the majority of the parts of a fetus can be harvested; from the
central nervous system for neural stem cells, to the skin for epidermal progenitors.20,21

4. Approaches for regeneration of the urogenital tract

In the past decade, several studies have focused on the use of regenerative medicine to correct
insufficiencies in the urogenital tract.

4.1 Stem/progenitor cell treatment of stress urinary incontinence (SUI)

Biomaterials aim to resolve SUI by providing structural/mechanical bladder neck support. This is
executed via the injection of autologous stem or urethral tract progenitor cells, which has been
culture–expanded before retransplantation, into the urethral sphincter. This aims to restore and
regenerate rhabdomyosphincter muscle content and function. Continuing clinical and animal studies
suggest that injected autologous cells may integrate into the sphincteric complex and differentiate,
leading to “sphincter regeneration”.22 However, it is unclear as to the precise fate of injected cells, such

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as the extent to which injected cells integrate and adopt a functional myogenic phenotype, or perform a
growth factor secreting feeder function to stimulate regeneration. Nevertheless, the concept of stem cell
injection for sphincteric muscle regeneration is the subject of research in a number of centres and the
development of improved forms of treatment for SUI might yet prove to be one of the major clinical
benefits of regenerative medicine.

4.2 Bladder reconstruction

A tissue–engineered and urothelial–lined bladder provides a functional barrier against urine exposure
and could help to overcome most of the serious complications associated with conventional
entero–cystoplasty. The requirements of such “engineered” tissue are more complex than just structural
support and need to fulfil the functions of the normal healthy bladder wall by combining compliance
(normally conferred by the detrusor smooth muscle) with a urinary barrier (normally provided by the
specialised urothelial lining).23
Three fundamentally different strategies have been investigated to augment or reconstruct the urinary
bladder:
● Use of acellular natural or synthetic biomaterials
With this approach an acellular biomaterial graft is used as a tissue implant which becomes
incorporated through the ingrowth of cells from the surrounding native host bladder. As
biomaterials can be produced, stored and used as “off–the–shelf” materials, this approach
circumvents technically demanding and expensive cell–based and patient–specific procedures. The
best studied of these biomaterials are small intestinal submucosa and bladder–derived acellular
matrix. Success varies with these materials and seems to be dependent on the graft size and
biomaterial processing.24
● Implantation of scaffolds pre–incubated with autologous cells in vitro
Tissue is engineered by seeding cultured cells (usually autologous urothelial and smooth muscle
cells) onto a biodegradable scaffold in vitro prior to implantation. In 2006, Atala et al.25 reported
the first clinical tissue–engineered bladder augmentation procedures in seven patients aged 4–19
years with neuropathic bladders in a follow up period ranging from 22–61 months. Autologous
urothelial cells from bladder biopsies were cultured in vitro for 7–8 weeks prior to seeding on
collagen or collagen coated polyglycolic acid (PGA) scaffolds. Biopsies taken from the engineered
augments showed “adequate structural architecture and phenotype” without causing metabolic
problems, urinary calculi or abnormal mucus production. Functional urodynamic data revealed
best outcomes in patients receiving cell–seeded collagen coated PGA scaffolds wrapped in omentum
as a vascular bed at the time of reconstruction. Although this is the first report indicating the
feasibility of creating a full thickness bladder wall from in vitro propagated urothelial and smooth
muscle cells in patients, important questions remain, particularly regarding the fate of the seeded
cells in the regenerated organ.
● Combining tissue–engineered urothelium with a host vascularised smooth muscle segment
(“composite cystoplasty”)
Composite cystoplasty describes an approach to combine autologous urothelial cell sheets grown
and expanded in vitro with a de–epithelialised pedicled smooth muscle segment from the host.26
There are advantages of this strategy over a completely tissue–engineered organ. The first is that the
in vitro component of the procedure is confined to the propagation of urothelium and the second
is that a single, highly regenerative cell type is combined with a preformed, vascularised smooth
muscle tissue. The rationale stems from long term complications of conventional entero–cystoplasty
which arise almost entirely from the unsuitable properties of the intestinal epithelium rather than
the smooth muscle component of the bowel wall.

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4.3 Biomaterials for pelvic floor prolapse (POP) and urinary incontinence (UI)
There are two distinct requirements of bioengineered materials in this area. The first requirement is to
provide mechanical support to the pelvic organs. The second is to generate new muscle which can perform
in an integrated manner with the existing organs, such as with new sphincters. The main disadvantages of
synthetic meshes for POP and pelvic floor related UI are the complications of erosion and extrusion.
Biomaterial developed to replace meshes would need to contain the strength of meshes and also be
bioabsorbable. Hybrid biomaterials may be fabricated using a combination of synthetic and naturally
derived polymers and can possess many desired characteristics of replacement tissues, including good
biocompatibility and appropriate biomechanical and biochemical properties. Fibre diameter can be altered
by changing the relative concentration of the two polymers, which in turn could be used in producing the
most appropriate biomaterial for use.27 In order to fulfil the aim of producing an optimised biomaterial for
restoring pelvic floor function and resolving SUI in all patients, further in vivo testing is essential.

4.4 Uterine reconstruction.

Factors that affect the integrity of the uterus, such as congenital/acquired malformations or disease, often
compromise a woman’s reproductive potential. As referenced earlier the uterus is a source of progenitor
cells that enhance the ability of self–repair.28 Studies by Taylor’s29 group have demonstrated that bone
marrow stem cells can engraft and produce endometrium from the beginning. This finding, and that of
Tanaka et al.30 regarding sustained engraftment of primate embryonic stem cells in the ovine uterus, suggest
that cell therapy may be used to regenerate uterine tissues for women with uterine factor infertility.

4.5 Vaginal reconstruction

The first–line treatment for vaginal agenesis is vaginal dilation therapy. However, vaginal reconstruction
is often performed as a treatment for vaginal agenesis using nonvaginal tissue substitutes, such as
segments of large intestine or skin. These materials are not functionally or anatomically ideal. Using a
rabbit model, De Filippo et al.31 reported the construction of a functional vagina using autologous cells
expanded from a small vaginal biopsy. Six months after total vaginal replacement, radiographic analysis
of rabbits implanted with the neo–vagina demonstrated wide, patent vaginal calibres without strictures.
Histological analysis revealed well organised epithelial and muscle cell layers. Physiological studies
showed normal range responses to electrical stimulation or to an adrenergic agonist.

5. Opportunities for intrauterine stem cell transplantation (IUSCT) for monogenic diseases

5.1 Rationale for IUSCT

The objective of IUSCT is to correct a genetic disorder early in the evolution of disease through the
engraftment of normal functional stem cells. There are several aims of IUSCT; replacing the missing or
aberrant protein before permanent organ damage occurs, rescuing an affected fetus from a
perinatally–lethal condition or improving postnatal survival and preserving vital functions. The fetal
milieu offers the best chance of cure for diseases that cause end–organ damage in utero, because of the
opportunity to correct pathology at the early stages of cellular damage. Tolerance toward the
transplanted cells may be induced in the pre–immune fetus before antigen–recognition develops at the
end of the first trimester, in order to facilitate engraftment in an immature bone marrow compartment
where there is little competition from host cells. Because of the physical limitation on the quantity of
donor stem cells that can be harvested and transplanted, fetal size offers a distinct advantage over the
several–fold larger neonate. This advantage is that it allows a greater concentration of stem cells to be
achieved within the target organ compared to a larger postnatal recipient. Potential target organs in early
development such as the central nervous system have a greater susceptibility to transduction by vectors
or engraftment by stem cells. This may be a function of the temporal appearance of cell surface receptors
and metabolic pathways. Restrictive barriers such as the blood–brain barrier are also more permissive in
early development which may contribute to more efficient stem cell engraftment in the fetus.32

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5.2 Applications of IUSCT
The most cogent argument for IUSCT would be to treat diseases which can result in perinatal lethality,
such as α–thalassaemia and those which cause irreversible end organ damage such as some
mucopolysaccharidoses (MPS). However, the ontological advantages, especially immune naiveté, which
allows for the use of normal allogeneic cells, will make this attractive to diseases of early postnatal onset,
such as β–thalassaemia and sickle cell anaemia, muscular dystrophies and other lysosomal enzyme
disorders (Appendix 1). Experimental data in small and large animals demonstrate varying degrees of
engraftment following IUSCT.33 Although, because genetic knockout large animal models are currently
unavailable, efficacy of this treatment in arresting or reversing pathology remains to be seen. Human
experience with in utero haematopoietic stem cell transplantation (IUHSCT), performed for a spectrum
of genetic diseases, informs us that successful treatment has only been achieved in a few fetuses with
inherited immunodeficiencies.34 The success is likely to be mainly due to the availability of a stem cell
niche and the lack of an immune response to the donor cells. IUSCT has been performed unsuccessfully
in fetuses with haemoglobinopathies or enzyme deficiency disorders at a time in gestation when
immune–competency had been attained. More information is required concerning the factors governing
the efficacy of IUSCT and obstacles to successful engraftment. Important barriers include a normal host
haemopoietic microenvironment that competitively inhibits donor stem cell proliferation in bone
marrow niches, explaining the success seen almost exclusively in immunodeficient syndromes.35 In mouse
models, maternal humoral or cell–mediated response to the transplanted cell or to the transgenic protein
can interfere with cell engraftment and transgene expression in transplanted fetuses.36,37 While this has
not been validated in large animal models, it is likely that the use of paternal HSC and the avoidance of
breastfeeding may be required to negate these immune barriers. Successful IUSCT will potentially negate
the need to find a haplo–identical allogeneic donor and avoid the myeloablative side effects associated
with postnatal bone marrow transplantation.
The use of hfMSC has been explored for diseases involving a mesenchymal origin, where they undergo
site–specific differentiation and contribute to the repair of the tissues after IUSCT with hfMSC in both
muscular dystrophy and osteogenesis imperfecta (OI) mouse models.38,39 While there was no cure in the
case of muscular dystrophy, hfMSC–IUSCT in a murine model of OI led to normalisation of bone
indices, and a two thirds reduction in fracture frequencies.40 Clinical transplantation of hfMSC in a case
of Type III OI resulted in a better than expected clinical outcome.41 A fetus with prenatally diagnosed OI
has been transplanted in utero in Singapore with preliminary results suggesting an augmentation of the
growth rates (Chan, personal communication). It is likely that this approach will be adopted as an
open–label Phase I trial.

5.3 Allogeneic versus autologous approaches

The fetus can be a recipient for autologous or allogeneic transplantation of HSC to treat monogenic
disorders which have been shown to benefit from bone marrow transplantation in the postnatal patient,
such as β–thalassaemia major, severe combined immunodeficiency (SCID) or selected lysosomal storage
disease (LSD).42–44 Allogeneic donor stem cells that are transplanted before the onset of fetal immune
maturity can achieve central tolerance and avoid rejection. An ex vivo gene transfer approach via the
harvest of autologous stem cells through fetal blood sampling or fetal liver biopsy in early gestation is
another approach. Here, defective autologous stem cells are corrected through gene transfer technologies
before reintroduction into the fetus, reducing the risk of immune rejection.45 Whilst this approach may
appear attractive, it may also present significant technical obstacles for clinical translation. This is because
it would require confirmation of pregnancy, molecular diagnosis, fetal stem cell harvesting, gene
correction and reintroduction into the fetus towards the end of the first/early second trimester window.
Experience with large animal models in this field has been limited to the fetal sheep model, where both
allogeneic and autologous first and second trimester fetal liver mononuclear cell transplantation resulted
in similar rates of engraftment. However, the harvest of these fetal liver cells through a 20G needle
resulted in a loss of 7 out of 15 (47%) fetuses. A published clinical series showed that ultrasound or

Scientific Impact Paper 38 6 of 11 © Royal College of Obstetricians and Gynaecologists

fetoscopy guided human fetal liver biopsies result in a far lower procedure–related pregnancy loss rate.46
Highly proliferative first trimester fetal HSC circulate in significant numbers, have favourable engraftment
kinetics, and are thus a possible source of autologous HSC. Although, only limited safety data has accrued
to date with 25–33% incidence of bradycardia and a loss rate between 5–8% at 12 weeks.45 Amniotic
fluid may be a feasible and safer alternative source if significant HSC numbers can be derived.47
5.4 Tissue engineering using fetal stem cells for specific intrauterine applications
Fetal stem cells, as a source of material for tissue bioengineering, have the potential for far–reaching
application. These applications include the utility of fetal mesenchymal stem cells for bone therapies,1 and
the potential application of amniotic membrane and fluid–derived stem cells for diseases of the skin, liver
and heart.48 Although a detailed discussion is not within the scope of this paper, stem cells derived from
fetal sources may have specific intrauterine application for sealing amniotic membranes following preterm
rupture or amniocentesis. They may also be a valuable source for developing autologous implants to be
used in reconstructive surgery for congenital heart disease, craniofacial and neural tube defects.50–52

6. Opinion
Stem cells from reproductive tissues have now been isolated and well characterised, with significant
advances made in directing their differentiation, genetic manipulation and integration into scaffolds
and bioreactors.
We are beginning to understand the potential role of regenerative medicine in the treatment of urogenital
diseases. The opportunity to widen such applications within reproductive medicine is becoming
apparent. Progenitor cells are likely to play an important role in normal uterine and ovarian physiology
and are probably involved in the response of these tissues to injury and disease. The potential to exploit
these processes for the fabrication of tissue or organ implants is promising, such as the utilisation of
urogenital tract cells in the construction of the urinary bladder. These cells may also be used as a platform
for in place organ regeneration. In addition, stem cells are likely to play a role in reproductive tract
pathology in some cancers, endometriosis and other diseases. Greater understanding of stem cell biology
and the processes that result in uncontrolled reproductive cell proliferation may prove helpful in the
treatment of these conditions and could yield novel alternatives to standard treatments for urinary
incontinence, infertility and structural repair.
In the field of obstetrics, particularly fetal medicine, the twin advances made in prenatal molecular
diagnosis and the advent of stem cell transplantation and ex vivo gene transfer may impact greatly in the
treatment of a wide range of inherited genetic disorders. Some clinical success has already been reported
for immunodeficiency disorders and skeletal dysplasia, while emerging data from preclinical models in
mice and in particular nonhuman primates will inform future clinical translation of this technology for
other genetic diseases. The first human experiments will commence where there is a strong clinical
indication for intervention, when the potential benefits outweigh putative risks and an understanding
that there may still be issues that cannot be addressed with animal models is in place. Given the burden
of β–globinopathies and the progress made in the preclinical field, it is likely that the
haemoglobinopathies will be one of the first diseases to reach broad clinical translation.
Women with a prenatal diagnosis of severe or lethal genetic disease are currently faced with the choice
of having an affected baby with only palliative postnatal therapy available or pregnancy termination and
possibly future pre–implantation genetic diagnosis and embryo selection. The heretofore unrealised
potential of IUSCT may be the only therapeutic option. On the other hand, there is limited evidence that
a complete cure can be achieved, and therapeutic benefit may only be seen after repeated pre and
postnatal dosing. Thus, partial IUSCT may alter the outcome from perinatal demise to survival of a
severely disabled child who would still require postnatal therapy. Bystander maternal effects will also be
an important consideration which may mitigate the desire to treat the fetus. Potential adverse effects may
be related to the procedure by which the material is injected, including transplacental cell trafficking.

Scientific Impact Paper 38 7 of 11 © Royal College of Obstetricians and Gynaecologists

The authors recommend that clinicians are aware of the various ethical issues at play when IUSCT is
contemplated. It is also recommended that a multidisciplinary approach is adopted with a transparent
discussion about the known limitations, putative benefits and unknown or unquantifiable risks. We
recommend that each clinical case be considered on its individual merits until there is a greater body of
evidence on the efficacy of fetal therapy from which to draft guidelines. Centres of excellence in fetal
medicine and therapeutics research should take the lead in developing the scientific expertise in this field
and the clinical guidelines for future trials, in discussion with the regulatory and ethical authorities.

References
1. Zhang ZY, Teoh SH, Hui JH, Fisk NM, Choolani M, Chan JK. The potential of human fetal
mesenchymal stem cells for off–the–shelf bone tissue engineering application. Biomaterials
2012;33:2656–72.
2. Portmann–Lanz CB, Schoeberlein A, Huber A, Sager R, Malek A, Holzgreve W,et al. Placental
mesenchymal stem cells as potential autologous graft for pre– and perinatal neuroregeneration.
Am J Obstet Gynecol 2006;194:664–73.
3. De Coppi P, Bartsch G Jr, Siddiqui MM, Xu T, Santos CC, Perin L, et al. Isolation of amniotic
stem cell lines with potential for therapy. Nat Biotechnol 2007;25:100–6.
4. Campagnoli C, Fisk N, Overton T, Bennett P, Watts T, Roberts I. Circulating hematopoietic
progenitor cells in first trimester fetal blood. Blood 2000;95:1967–72.
5. Robin C, Bollerot K, Mendes S, Haak E, Crisan M, Cerisoli F, et al. Human placenta is a
potent hematopoietic niche containing hematopoietic stem and progenitor cells throughout
development. Cell Stem Cell 2009;5:385–95.
6. Chan J, Kumar S, Fisk NM. First trimester embryo–fetoscopic and ultrasound–guided fetal
blood sampling for ex vivo viral transduction of cultured human fetal mesenchymal stem cells.
Hum Reprod 2008;23:2427–37.
7. Zhang ZY, Teoh SH, Chong MS, Schantz JT, Fisk NM, Choolani MA, et al. Superior
osteogenic capacity for bone tissue engineering of fetal compared with perinatal and adult
mesenchymal stem cells. Stem Cells 2009;27:126–37.
8. Guillot PV, Gotherstrom C, Chan J, Kurata H, Fisk NM. Human first–trimester fetal MSC
express pluripotency markers and grow faster and have longer telomeres than adult MSC.
Stem Cells 2007;25:646–54.
9. Chan J, O'Donoghue K, Gavina M, Torrente Y, Kennea N, Mehmet H, et al. Galectin–1
induces skeletal muscle differentiation in human fetal mesenchymal stem cells and increases
muscle regeneration. Stem Cells 2006;24:1879–91.
10. Chong MS, Chan J. Lentiviral vector transduction of fetal mesenchymal stem cells. Methods
Mol Biol 2010;614:135–47.
11. Götherström C. Immunomodulation by multipotent mesenchymal stromal cells.
Transplantation 2007;84 (Suppl 1):35–7.
12. Mayani H, Lansdorp PM. Biology of human umbilical cord blood–derived hematopoietic
stem/progenitor cells. Stem Cells 1998;16:153–65.
13. Musina RA, Bekchanova ES, Belyavskii AV, Grinenko TS, Sukhikh GT. Umbilical cord blood
mesenchymal stem cells. Bull Exp Biol Med 2007;143:127–31.
14. Yin Y, Ren HY, Cen XA, Qiu ZX, Ou JP, Wang WS, et al. Long–term outcomes in adults with
leukemia treated with transplantation of two unrelated umbilical cord blood units. Chin Med J
(Engl) 2011;124:2411–6.
15. Royal College of Obsetricians and Gynaecologists. Umbilical Cord Blood Banking (SAC
Opinion Paper 2). London;RCOG:2007.
16. Committee on Obstetric Practice, Committee on Genetics. ACOG committee opinion number
399, February 2008: umbilical cord blood banking. Obstet Gynecol 2008;111:475-7.
17. Reed W, Walters M, Trachtenberg E, Smith R, Lubin BH. Sibling donor cord blood banking
for children with sickle cell disease. Pediatr Pathol Mol Med 2001;20:167–74.

Scientific Impact Paper 38 8 of 11 © Royal College of Obstetricians and Gynaecologists

18. Mattar CN, Biswas A, Choolani M, Chan JK. The case for intrauterine stem cell
transplantation. Best Pract Res Clin Obstet Gynaecol 2012;26:683–95.
19. Sensebé L, Bourin P, Tarte K. Good manufacturing practices production of mesenchymal
stem/stromal cells. Hum Gene Ther 2011;22:19–26.
20. Ribeiro D, Laguna Goya R, Ravindran G, Vuono R, Parish CL, Foldi C, et al. Efficient
expansion and dopaminergic differentiation of human fetal ventral midbrain neural stem cells
by midbrain morphogens. Neurobiol Dis 2012;49C:118–27.
21. Johnen C, Chinnici C, Triolo F, Plettig J, Brautigam K, Amico G, et al. Phenotypical
characterization of 6–21–week gestational age human dermis and epidermal cell isolation
methods for in vitro studies on epidermal progenitors. Burns 2013;39:300-10.
22. Smaldone MC, Chen ML, Chancellor MB. Stem cell therapy for urethral sphincter
regeneration. Minerva Urol Nefrol 2009;61:27–40.
23. Aboushwareb T, Atala A. Stem cells in urology. Nat Clin Pract Urol 2008;5:621–31.
24. Akbal C, Lee SD, Packer SC, Davis MM, Rink RC, Kaefer M. Bladder augmentation with
acellular dermal biomatrix in a diseased animal model. J Urol 2006;176:1706–11.
25. Atala A, Bauer SB, Soker S, Yoo JJ, Retik AB. Tissue–engineered autologous bladders for
patients needing cystoplasty. Lancet 2006;367:1241–6.
26. Fraser M, Thomas DF, Pitt E, Harnden P, Trejdosiewicz LK, Southgate J. A surgical model of
composite cystoplasty with cultured urothelial cells: a controlled study of gross outcome and
urothelial phenotype. BJU Int 2004;93:609–16.
27. Tillman BW, Yazdani SK, Lee SJ, Geary RL, Atala A, Yoo JJ. The in vivo stability of electrospun
polycaprolactone–collagen scaffolds in vascular reconstruction. Biomaterials 2009;30:583–8.
28. Maruyama T, Masuda H, Ono M, Kajitani T, Yoshimura Y. Human uterine stem/progenitor
cells: their possible role in uterine physiology and pathology. Reproduction 2010;140:11–22.
29. Du H, Taylor HS. Stem cells and female reproduction. Reprod Sci 2009;16:126–39.
30. Tanaka Y, Nakamura S, Shibata H, Kishi Y, Ikeda T, Masuda S, et al. Sustained macroscopic
engraftment of cynomolgus embryonic stem cells in xenogeneic large animals after in utero
transplantation. Stem Cells Dev 2008;17:367–81.
31. De Filippo RE, Bishop CE, Filho LF, Yoo JJ, Atala A. Tissue engineering a complete vaginal
replacement from a small biopsy of autologous tissue. Transplantation 2008;86:208–14.
32. Mattar CN, Choolani M, Biswas A, Waddington SN, Chan JK. Fetal gene therapy: recent
advances and current challenges. Expert Opin Biol Ther 2011;11:1257–71.
33. Shields LE, Gaur LK, Gough M, Potter J, Sieverkropp A, Andrews RG. In utero hematopoietic
stem cell transplantation in nonhuman primates: the role of T cells. Stem Cells 2003;21:304–14.
34. Choolani M, Chan J, Fisk NM. Fetal therapy: 2020 and beyond. Prenat Diagn 2010;30:699–701.
35. De Santis M, De Luca C, Mappa I, Cesari E, Quattrocchi T, Spagnuolo T, et al. In–utero stem
cell transplantation: clinical use and therapeutic potential. Minerva Ginecol 2011;63:387–98.
36. 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;121:582–92.
37. 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;119:2590–600.
38. Guillot PV, Cook HT, Pusey CD, Fisk NM, Harten S, Moss J, et al. Transplantation of human
fetal mesenchymal stem cells improves glomerulopathy in a collagen type I alpha 2-deficient
mouse. J Pathol 2008;214:627-36.
39. Panaroni C, Gioia R, Lupi A, Besio R, Goldstein SA, Kreider J, et al. In utero transplantation of
adult bone marrow decreases perinatal lethality and rescues the bone phenotype in the knockin
murine model for classical, dominant osteogenesis imperfecta. Blood 2009;114:459–68.
40. Guillot PV, Abass O, Bassett JH, Shefelbine SJ, Bou–Gharios G, Chan J, et al. Intrauterine
transplantation of human fetal mesenchymal stem cells from first trimester blood repairs bone
and reduces fractures in osteogenesis imperfecta mice. Blood 2008;111:1717–25.

Scientific Impact Paper 38 9 of 11 © Royal College of Obstetricians and Gynaecologists

41. Le Blanc K, Götherström C, Ringden O, Hassan M, McMahon R, Horwitz E, et al. Fetal
mesenchymal stem cell engraftment in bone following in utero transplantation in a patient
with severe osteogenesis imperfecta. Transplantation 2005;79:1607–14.
42. Aiuti A, Roncarolo MG. Ten years of gene therapy for primary immune deficiencies.
Hematology Am Soc Hematol Educ Program 2009:682–9.
43. Boztug K, Schmidt M, Schwarzer A, Banerjee PP, Díez IA, Dewey RA, et al. Stem–cell gene
therapy for the Wiskott–Aldrich syndrome. N Engl J Med 2011;363:1918–27.
44. Cavazzana–Calvo M, Payen E, Negre O, Wang, G, Hehir K, Fusil F, et al. Transfusion
independence and HMGA2 activation after gene therapy of human β–thalassaemia. Nature
2010;467:318–22.
45. Chan J, Kumar S, Fisk NM. First trimester embryo–fetoscopic and ultrasound–guided fetal
blood sampling for ex vivo viral transduction of cultured human fetal mesenchymal stem cells.
Hum Reprod 2008;23:2427–37.
46. Shulman LP, Elias S. Percutaneous umbilical blood sampling, fetal skin sampling, and fetal
liver biopsy. Semin Perinatol 1990;14:456–64.
46. Shaw SW, Bollini S, Nader KA, Gastadello A, Mehta V, Filppi E, et al. Autologous
transplantation of amniotic fluid–derived mesenchymal stem cells into sheep fetuses. Cell
Transplant 2011;20:1015–31.
48. Rennie K, Gruslin A, Hengstschläger M, Pei D, Cai J, Nikaido T, et al. Applications of
amniotic membrane and fluid in stem cell biology and regenerative medicine. Stem Cells Int
2012;2012:721538.
49. Mi S, David AL, Chowdhury B, Jones RR, Hamley IW, Squires AM, et al. Tissue engineering a
fetal membrane. Tissue Eng Part 2012;18:373–81.
50. Weber B, Zeisberger SM, Hoerstrup SP. Prenatally harvested cells for cardiovascular tissue
engineering: fabrication of autologous implants prior to birth. Placenta 2011;32 (Suppl 4):316–9.
51. Turner CG, Klein JD, Gray FL, Ahmed A, Zurakowski D, Fauza DO. Craniofacial repair with
fetal bone grafts engineered from amniotic mesenchymal stem cells. J Surg Res 2012;178:785–90.
52. Turner CG, Klein JD, Wang J, Thakor D, Benedict D, Ahmed A, et al. The amniotic fluid as a
source of neural stem cells in the setting of experimental neural tube defects. Stem Cells Dev
2013;22:548-53.

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Appendix 1. Summary of potential candidate diseases for IUSCT

Disease type Disease Aberrant Postnatal treatment IUSCT

gene/protein with stem cell attempted in
transplant human fetuses?
recommended?
Haemoglobinopathies α–thalassaemia α–globin Yes Yes
β–thalassaemia β–globin Yes Yes
Sickle cell disease HbS Yes Yes

Lysosomal storage MPS I a–l–iduronidase Yes Yes

disease (Hurler syndrome)
MPS VI Arylsulfatase B Yes, for severe disease No
MPS VII β–glucuronidase Yes No
X–linked ABCD1 gene Yes, for cerebral X–ALD No
Adrenoleukodystrophy
Globoid–cell GALC gene Yes No
leukodystrophy
Gaucher disease β–glucosidase Type 1 only No
Niemann Pick disease SMPD1 gene Type B only Yes

Immunodeficiency X–SCID IL–2Rγ (common Yes Yes

syndromes gamma chain)
ADA–SCID adenosine Yes No
deaminase
Chronic granulomatous p91–PHOX Yes Yes
disease (CGD)

Genetic bone disorder Osteogenesis imperfecta COL1A1 No Yes (hfMSC)

This Scientific Impact Paper was produced on behalf of the Royal College of Obstetricians and
Gynaecologists by:
Professor AJ Atala MD, The Wake Forest University Institute for Regenerative Medicine ,
Wake Forest School of Medicine, North Carolina, USA; Dr JKY Chan MRCOG, Singapore;
Dr M Choolani FRCOG, Singapore; Dr CN Mattar MBBS MRANZCOG MMED,
National University Hospital (NUH) Women’s Centre, NUH, Singapore and
Professor JK Williams DVM, The Wake Forest University Institute for Regenerative Medicine,
Wake Forest School of Medicine, North Carolina, USA
and peer–reviewed by:
British Society of Urogynaecology (BSUG); Dr C Connon BSc PGDip PhD, School of Pharmacy,
University of Reading, Reading; Miss SM Creighton FRCOG, London and
Professor AP Murdoch FRCOG, Newcastle.
The Scientific Advisory Committee lead reviewer was:
Professor RA Anderson FRCOG, Edinburgh.
The final version is the responsibility of the Scientific Advisory Committee of the RCOG.

The review process will commence in 2016, unless otherwise indicated.

Scientific Impact Paper 38 11 of 11 © Royal College of Obstetricians and Gynaecologists