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GENERAL GYNECOLOGY
Stem cells in gynecology
Felicia L. Lane, MD; Stephanie Jacobs, MD
FIGURE 1
Variation in potency of stem cell types
sphincters both contain skeletal muscle Some of the earliest research using model was published in 2000.7 Chancellor
that contributes to effective continence. myoblasts was in the field of Duchenne et al7 demonstrated histologic evidence of
However, age-related changes, injury, Muscular Dystrophy. The concept of cell survival and fusion of myoblasts to
and trauma can all lead to compromise muscle biopsy, in vitro culture, and sub- myotubes after periurethral injection.
in function. Skeletal muscle possesses the sequent myoblast transplant to treat this Translation to anal incontinence models
ability of inherent regeneration based on degenerative disorder was proposed in ensued. Kang et al8 and Lorenzi et al9 pub-
the presence of satellite cells. Satellite 1978. Multiple animal studies ensued lished some of the earliest work transplant-
cells exist below the basal lamina in a through the 1980s, and in 1990 the first ing stem cells into injured rat anal sphinc-
dormant state, and on injury are acti- human myoblast transplant occurred. ters. Improved function was demonstrated.
vated and act as native reparative cells. Unfortunately, success was limited, pos-
Activated satellite cells produce myo- sibly because of the nature of this sys- Potential benefits of stem
blasts— unipotent muscle progenitor temic degenerative disorder and large cell use in gynecology
stem cells (Figure 2). Myoblasts fuse to burden of muscular dysfunction. In ad- Use of stem cells for the treatment of uri-
form myotubes, and myotubes are pack- dition, transplanted cells presented an nary and anal incontinence holds great
aged into sarcomeres and align to form overwhelming challenge of rapid cell promise especially when considering
myofibers. This process ultimately leads death and migration.6 Incontinence that existing options for both remain
to muscle regeneration. Unfortunately, models built on this concept, and possi- limited. Stress urinary incontinence
in the native state, the portion of satellite bly because they involve a smaller muscle (SUI) can be attributed to either loss of
cells within skeletal muscle is quite burden, have demonstrated greater prom- urethral support and resulting hypermo-
small— unable to compensate for large ise. Proof of concept of myoblast trans- bility, intrinsic deficiency within the ure-
or chronic injuries alone.6 plantation in a rat stress incontinence thral sphincter (ISD), or a combination
of both. To date SUI can be effectively
FIGURE 2 treated with surgical placement of a
Native satellite cells produce myoblasts upon injury/activation midurethral sling. Treatment of sphinc-
teric dysfunction presents a greater chal-
lenge. Urethral bulking can help to re-
store coaptation, but long-term efficacy
is lacking and local tissue reaction can
occur.10 Effective treatment options for
anal incontinence are even more sparse.
Physical therapy can provide modest ben-
efit. Sphincteroplasty, bulking agents,
and/or artificial sphincters have poor long-
term outcomes and can pose significant
risks of infection.11
As both SUI and anal incontinence
In the natural state, satellite cells reside below the basal lamina of skeletal muscle. At times of injury, (AI) can result from loss of muscular in-
these cells are activated and produce unipotent myoblast cells which act as stem cells and aid in tegrity and function, rebuilding muscle
muscular regeneration. from a cellular level represents an ideal
Lane. Stem cells. Am J Obstet Gynecol 2012. treatment concept. Numerous animal,
along with a few human studies, have, in
fact, demonstrated functional measures cally studied immune modulation, de- ment in 26 of 39 women with SUI who were
of success. As stem cell research has ex- creases in inflammation could improve injected transurethrally at 4 and 8 o’clock
panded, theories accounting for the tissue healing. with human umbilical cord stem cells. And,
mechanism of action have expanded as Another point of variation among SUI most recently, 12 women with severe SUI
well. Initially, the theory was that trans- studies is the method of injury used to create andafixedurethrareceivedinjectionofmus-
planted cells would engraft, differentiate, animal models of urinary incontinence. This cle progenitor cells derived from autologous
and directly lead to functional regenera- includes pudendal or sciatic nerve transec- deltoid biopsy. Cells were transplanted via
tion. Potential explanations now in- tion, crush nerve injury, urethral cyro- or single injection under endoscopic guidance.
clude: (1) direct stem cell engraftment chemoinjury, and vaginal distention. Precise Three women were dry at 12 months based
and muscle regeneration; (2) localized comparisons are difficult; still, studies have on self-reported diary and pad test measures.
bulking impact; (3) trophic effect be- shown definite trends toward improved out- Seven women had improved pad tests, but
cause of stem cell growth factor secre- come measures. not improved diary measures. Two women
tion; and (4) immune modulation af- For this review, we attempt to evaluate
demonstrated slight worsening of inconti-
fording improved tissue healing. These studies with similar methodologies in
nence.23 There were no adverse events en-
will be addressed in further detail below. conjunction. To begin, 2 studies, Xu et al
countered in any human study. Limitations
in 201014 and Kim et al in 2011,12 dem-
of human and animal studies include small
SUI onstrated full restoration of leak point
pressures (LPP) in a rat model after ure- sample sizes and/or lack of control groups
Stem cell research for the treatment of and randomization (Table 1).
SUI is rapidly expanding with overall en- thral injections of BMSC postpudendal
nerve transection. Kinebuchi et al24 fur- As mentioned, multiple theories exist for
couraging results.10,12-25 Bone marrow how stem cells function to improve stress in-
(BMSC) and adipose-derived mesen- ther demonstrated a trend toward LPP
restoration when BMSC were injected continence.Again,possibilitiesincludedirect
chymal stem cells (ADSC) are the most cell integration and muscular regeneration,
into rat urethras after urethrolysis and
common cell populations used in mu- bulking effect, trophic impact, and/or im-
localized toxic injection. Although re-
rine transplants, although muscle-de-
sults did not reach significance, it is im- mune modulation. Murine studies have typ-
rived stem cells (MDSC) (cultured from
portant to note that this last model of icallyusedlabeledcelltransplantations(most
patient thigh or deltoid biopsies) have
injury was extensive and may represent a commonlyGFP).Themajorityhavesuccess-
typically been used in human stud-
more severe presentation of inconti- fully demonstrated labeled cell presence on
ies.21,23 The ideal cell population has yet
nence. Furthermore on histologic evalu- histologic examination.12-17 Such findings
to be determined.
ation, Kinebuchi et al24 did demonstrate supported initial theories of direct cell inte-
Transplantation method of cells has
significantly more striated muscle in the gration, differentiation and muscle regener-
also varied, and has included intraure-
transplantation group than in controls. ation. Still, on closer examination, some of
thral, periurethral, and intravenous (IV) Three recent studies that used ADSC for thesesamestudiesfoundasignificantdecline
routes. Localized injections make inher- transplant have also shown benefit. In the
ent sense, IV injection methods, on the in cell presence over time—as rapidly as 10
first,20ratsweretransplantedafterpudendal days.13 In Lim et al’s work,18 labeled human
other hand, less so. The method of IV crush injury. Follow-up measures demon-
transplantation is based on stem cell umbilical cord blood cells were present at 2
strated increased LPP, closure pressure, and weeks, but absent at 4—interestingly, this
homing ability. For example, after simu- functional urethral lengths compared with
lated injury with pelvic floor distention, was in direct contrast to the time frame of
controls.16 Lin et al19 demonstrated that ro- histologic improvement. In addition, Lin et
IV injected stem cells were found to mi- dents receiving stem cell transplants had re-
grate and ultimately accumulate within al19 found labeled ADSC 4 weeks after trans-
duced voiding dysfunction (33% vs 80% in
the injured pelvis.13 Benefits of IV ad- plantation. However, they found lack of cell
controls)aftervaginaldistension.Zhaoetal20
ministration could include: a less inva- differentiation, and thereby determined cells
found that inclusion of encapsulated nerve
sive route when compared with multiple did not successfully engraft. Benefit in func-
growth factor (NGF) with ADSC transplant
direct tissue injections, and/or could po- successfully increased cell survival, differenti- tion, Lim et al18 and Lin et al19 concluded,
tentially maximize cell delivery to the lo- ation, and neuronal density. was likely because of trophic factors rather
cation of greatest impact if they are con- Other researchers have begun to bridge than direct stem cell muscle regeneration.
sistently found to, in fact, home to the the gap to human studies. In the earliest Other studies have supported efficacy via
site of injury. This has yet to be clarified publication, 8 women received autologous bulking effect. Kim et al12 and Xu et al14 re-
in the literature. In addition, studies have MDSCs (thigh muscle biopsy) in up to 4 cir- ported evidence of “muscular masses” and
reported successful immune modulation cumferential periurethral injections. Of the 5 increased muscle thickness in rat urethras af-
with IV injected mesenchymal cells. Sev- women available for follow up, all had im- ter transplantation. This could provide more
eral clinical trials are examining IV mes- provement (although 2 eventually under- of an obstructive rather than functional
enchymal infusions to treat a wide range went midurethral sling placement), and 1 re- method of improved continence. Questions
of autoimmune disorders.26 Although ported total continence.21 Lee et al22 remainregardingtheexactmechanismofac-
incontinence research has not specifi- demonstrated ⬎50% subjective improve- tion, but overall a trend toward benefit exists.
TABLE 1
Summary stem cell research in stress urinary incontinence
Author Cell source Methods Results/conclusions Complications
12
Kim et al Rat BMSC Rat population Restoration LPP/CP in transplant None
Injury: bilateral pudendal group Presence “muscle
nerve transection Muscle masses noted in urethra masses” noted
Injection: periurethral Conclude efficacy could be due
4 wk outcome measures to improved contraction ⫾
bulking effect
................................................................................................................................................................................................................................................................................................................................................................................
Cruz et al13 Rat BMSC labeled with GFP Rat population 4 d: GFP in urethra, vagina, None
Injury: vaginal distension rectum, and levator
Injection: IV 10 d: increased GFP in urethra
4 and 10 d outcome IV BMSC able to home to sites of
measure injury
................................................................................................................................................................................................................................................................................................................................................................................
Xu et al14 Rat MDSC labeled w Rat population Transplant: LPP increased with None
GFP ⫾ Fibrin Glue Injury: bilateral pudendal and without fibrin glue vs injury Transplant group: ⫹
transection without transplant increased thickness of
Injection: periurethral No significant difference in muscle with variable fiber
1, 4 wk functional function with fibrin glue, but ⫹ orientation
evaluation increased cell survival and
4 wk histology microvessel density
................................................................................................................................................................................................................................................................................................................................................................................
Corcos et al15 Rat BMSC Rat population Resolution of LPP to baseline in None
Injury: bilateral pudendal Transplant group
transection
Injection: intrasphincteric
4 wk postevaluation
................................................................................................................................................................................................................................................................................................................................................................................
Wu et al16 Rat ADSC Rat population Transplantation group: increased None
Injury: pudendal nerve LPP, CP, FUL, vs no transplant
(crush) Urethra: structural resolution to
Injection: periurethral, 3 baseline with transplantation
sites
Sacrifice at 3, 7, 14 d
posttransplantation
................................................................................................................................................................................................................................................................................................................................................................................
Lim et al18 HUCB with fluorescent label Rat population Transplants: LPP and histologic None
Injury: periurethral improvement vs control
electrocautery BUT no labeled cells found at
Injection: 2 sites, lateral 4 wk
wall midurethra Impact attributed to paracrine
Evaluation 2, 4 wk effect of cytokines and growth
factors
................................................................................................................................................................................................................................................................................................................................................................................
19
Lin et al Rat ADSC, labeled Rat population Significant improvement in LPP None
Injury: vaginal distension with either transplantation
and bilateral oopherectomy method
Injection: intraurethral or IV ⫹ Detection cells at 4 wk
Evaluation at 4 wk ⫹ Homing demonstrated in IV
transplantation
................................................................................................................................................................................................................................................................................................................................................................................
Zhao et al20 Rat ADSC rat ⫾ nerve Rat population Significant improvement LPP and None
growth factor (NGF) ⫾ Injury: bilateral pudendal muscle proportion and neuronal
encapsulated polylactic- transection density when ADSC ⫹ NGF ⫹
coglycolic acid Injection: periurethral Capsule
Evaluation at 8 wk Other ADSC groups improved but
did not return to baseline
................................................................................................................................................................................................................................................................................................................................................................................
Kinebuchi et al24 Rat BMSC Rat population LPP increased in transplant None
Also injected 1 group with Injury: urethrolysis and group, but not significant vs CFM
CFM injection toxin injection
Injection: periurethral ⫹GFP showed fusion
13 wk evaluation Less striated muscle in CFM vs
MSC or control group
Some contribution growth
factors/cytokines from medium
alone seen
................................................................................................................................................................................................................................................................................................................................................................................
Lane. Stem cells. Am J Obstet Gynecol 2012. (continued )
TABLE 1
Summary stem cell research in stress urinary incontinence (continued)
Author Cell source Methods Results/conclusions Complications
10
Imamura et al Rabbit BMSC Rabbit population LPP higher in transplant vs None
Injury: cryoinjury control at 2 wk
Injection: intraurethral
Evaluation at 1, 2 wk
................................................................................................................................................................................................................................................................................................................................................................................
25
Fu et al Rat ADSC Rat population Max bladder capacity, LPP, and None
Injury: vaginal distention muscle thickness increased in
Injection: posterior urethra transplant group
at bladder neck
Follow-up 1, 3 mo
................................................................................................................................................................................................................................................................................................................................................................................
Carr et al 21
Autologous MDSC Human: 8 women SUI 5 women ⫹ improvement None
Injection: up to 4 1 woman ⫽ total continence
circumferential urethral 2 of the improved still proceeded
injections with midurethral sling
12 mo data 3 did not continue follow-up
................................................................................................................................................................................................................................................................................................................................................................................
22
Lee et al Human cord blood Human: 39 women w/SUI 12 months: 26 women (72.2%) None
Injection: transurethral had ⬎50% improvement
1, 3, 12 mo follow-up In selection of 10 women, MUCP
increased ⬎30 cm H2O
................................................................................................................................................................................................................................................................................................................................................................................
23
Sebe et al Autologous muscle Human: 12 women 3 patients dry: subjective diary None
progenitor cells persistent, severe SUI w and pad test
fixed urethra s/p prior failed 7 decreased with pad test, but
surgery no change after incontinence
Injection: intrasphincteric episodes 2 some worsening
Follow-up to 12 mo
................................................................................................................................................................................................................................................................................................................................................................................
ADSC, adipose derived mesenchymal stem cells; BMSC, bone marrow-derived mesenchymal stem cells; CFM, cell free medium; CP, closure pressure (urethral); FUL, functional urethral length; GFP,
green fluorescent protein; HUCB, human umbilical cord blood; LPP, leak point pressure; MDSC, muscle derived stem cells; NGF, nerve growth factor; SUI, stress urinary incontinence.
Lane. Stem cells. Am J Obstet Gynecol 2012.
AI and MDSC for the treatment of AI and 2 tude was higher in the MDSC group but not
AI is not uncommon. It is estimated to studies on MSCs.8,9,31-35 Our laboratory significantly.8 White et al,32 demonstrated
affect 2-15% of the general popula- published proof of concept that transplanted improved twitch tension, maximal titanic
tion.27,28 In women AI is often the result MDSC labeled with GFP can survive and contraction, and maximal contractile force
of an injury to the anal sphincter sus- fuse with host anal sphincter muscle (Figure in response to electrical field stimulation in
tained during childbirth. Approximately 3). In addition, 3 animal studies have looked rodents treated with myogenic stem cells vs
0.7-19.3% of vaginal deliveries can result at in vitro function of transplanted muscle controls. Work by Kajbafzadeh33 and
in anal sphincter laceration.29 Despite after euthanasia. Lorenzi et al9 divided 24 Aghaee-Afshar34 looked at the use of stem
postpartum identification and repair the WistarFurthratsinto3experimentalgroups. cells transplantation in a chronic sphincter
imaging supplement to the Childbirth and Group A underwent a sham operation, injury model. Animals in these studies un-
Pelvic Symptoms (CAPS) study demon- group B had sphincterotomy and repair of derwent sphincterotomy without subse-
strates greater than 50% of sphincter de- both anal sphincters plus saline injections,
quent repair. Stem cell transplantation was
fects will persist.30 and group C underwent sphincterotomy
performed 2-3 weeks status postinjury. Ani-
The mechanism of sphincter injury may and repair, followed by intrasphincteric in-
malswereeuthanizedatvaryingintervalsand
be due to muscle rupture, prolonged hyp- jection of bone-marrow-derived mesenchy-
histology and functional studies performed.
oxia and denervation, faulty repair, or a mal stem cells. All animals were euthanized
Histology revealed decreased fibrosis in the
combination of factors. Unfortunately, on day 30, histology and in vitro contractility
long-term success rates for primary or sec- assessed. Study results demonstrated that transplanted animals and improved mean
ondary sphincteroplasty are dismal with bone-marrow-derived mesenchymal stem anal resting pressures as well as improved
only 30% of patients demonstrating conti- cell transplants led to greater sphincter mus- anal sphincter electrical activity. No adverse
nence 5 years after surgery.30 cle area and improved contractility of muscle outcomes were described; however, 6 ani-
Myoblasts, MDSCs, and mesenchymal fibers in vitro.9 Kang et al,8 created a cryoin- mals died perioperatively in the Aghaee-Af-
stem cells (MSC) are promising potential jurywithintheanalsphincter,followedbyin- shar study. The authors commented that
therapies for AI. Since 2008, 5 peer-reviewed jection of MDSC and in vitro contractility these deaths appeared unrelated to the stem
articles have been published on myoblasts testing postmortem. The contraction ampli- cell transplants.33,34 Currently, there are no
TABLE 2
Summary stem cell research in anal incontinence
Author Cell Source Methods Results/conclusions Complications
31
Craig et al Rat myoblast No injury Evidence of fusion cells None
3 injections: 3 and 9 o’clock in all animals
................................................................................................................................................................................................................................................................................................................................................................................
8
Kang et al MDSC Cryoinjury Contractility cryoinjured None
3 injections into right ⬍ control (P ⬍ .05)
hemisphere anal sphincter Contractility MDSC
improved vs cryoinjured
(not significant)
................................................................................................................................................................................................................................................................................................................................................................................
9
Lorenzi et al Rat MSC Sphincterotomy with repair MSC improved muscle None
2 injections into either end regeneration and
sphincter increased contractile
function after sphincter
injury and repair
................................................................................................................................................................................................................................................................................................................................................................................
32
White et al Rat myoblast Sphincterotomy with repair Stem cell injection with None
bilateral sphincter injections repair improved function
at D 7 and 90 vs control
Unrepaired w/transplant:
no improvement
................................................................................................................................................................................................................................................................................................................................................................................
33
Kajbafzadeh et al Rabbit myoblast Sphincterotomy without repair Myoblasts accelerated None
Injection to injury site 3 wk repair and improved Noted regenerating
postop mean resting pressures muscle at 4 wks with
fibers in variable
orientation
................................................................................................................................................................................................................................................................................................................................................................................
35
Frudinger et al Human myoblast Chronic injury Squeeze pressures None
12-14 injections into external increased at 1 and 6 mo
sphincter but returned to baseline
at 12 mo.
Improved Wexner and
QOL
................................................................................................................................................................................................................................................................................................................................................................................
34
Aghaee-Afshar et al HUCM and rabbit MSC Sphincterotomy without repair 4/7 MSC and 2/7 in 6 rabbits died
Injection to injury site 2 wk HUCM with competent Reported complications
postop EAS unlikely due to stem
EMG frequency improved cell injections
in MSC group
................................................................................................................................................................................................................................................................................................................................................................................
HUCM, human umbilical cord matrix; MDSC, muscle-derived stem cells; MSC, mesenchymal stem cells; QOL, quality of life measures.
Lane. Stem cells. Am J Obstet Gynecol 2012.
vaginal fistula in a small group of women.43 ment options for affected individuals is ders. Before clinical application, further
Furthermore, researchers have proposed use of paramount importance. functional and safety studies are needed.
of seeded grafts to repair pelvic organ pro- Stem cell therapy holds a great deal of Priorities are as follows: (1) optimization
lapse. Perhaps stem cells and scaffolds could promise, excitement, and in some cases, of the stem cell source; (2) creation of a
allowsurgeonstomoveawayfrommeshand controversy. This review of the literature standardized cell harvest and culture
complications related to permanent materi- demonstrates that stem cells used in uri- protocol safe for human use; (3) deter-
als. These and perhaps other gynecologic nary and AI likely possess the ability to: (1) mination of maximum and minimum
conditions could benefit from stem cell engraft following transplantation; (2) im- therapeutic dosages; and (4) establish-
augmentation. prove function through bulking effect; (3) ment of a best practice transplantation
Comment elicit trophic effects on the host; and (4) route and technique. Once researchers
Pelvic floor disorders (pelvic organ pro- modulate inflammation. These properties overcome these hurdles, stem cell thera-
lapse, urinary and anal incontinence) result in beneficial histologic, functional, peutics may become a clinical reality. f
can affect up to 23% of the population.29 and clinical outcomes. However, the exact
The prevalence of these conditions in- mechanisms of repair are complex and not
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