Table 2 Selected preclinical studies using stem cell transplantation for sphincter dysfunctions

Urethral sphincter

 Evaluated the effects of MDC/BMSC co-transplantation into the urethra for SUI

Goats/ adult/aged, multiparous

29.6 × 106 goat MDC/ BMSC / Intraurethral injection [113]

↑ UPP,

↑ Ske-M

MDC/BMSC co-transplantation provides a greater chance of improvement in urethral closure than transplantation of each population alone

 Determined whether allogenic MDC could restore sphincter function

Rats/ cauterized urethra

1.5 × 106 rat MDC/ Intraurethral injection [231]

↑ LPP,

↑ Ske-M,

↑ Peri-N

Injection of intraurethral MDC improved sphincter function in rats with intrinsic sphincter deficiency

 Determined if increasing numbers of MSC improves urethral and pudendal nerve function and anatomy

Rats/ PNC + VD

one, two, or three doses of 2 × 106 rat BMSC/ IV [75]

↑ LPP,

↑Ske-M, ↑Sm-M, ↑Peri-N

MSC therapy for postpartum incontinence and SUI can be enhanced with multiple doses

 Assessed the effect of BMSC on LPP changes in a rat model of SUI

Rats/ PNC

1 × 106 rat BMSC/ Periurethral injections [114]

↑ LPP,

↑Ske-M

Periurethral injection of MSC in an animal model of SUI restored the damaged external urethral sphincter

 Evaluated functional and histological recovery by autologous BMSC transplantation into injured urethral sphincters

Rats/ urethral sphincters injury by urethrolysis and cardiotoxin injection

2.0–5.0 × 105 rat BMSC/ Periurethral injections [76]

↑Bladder capacity,

↑ Ske-M, ↑ Peri-N, but no changes in LPP

A trend towards recovery of LPP in BMSC-transplanted urethras

 Investigated the injected autologous ASC in improving SUI

Rats/ VD

2.0–5.0 × 105 rat ASC/ Periurethral injections [77]

↑ LPP,

↑ Bladder capacity,

↑Ske-M, ↑Sm-M,

↑ Vas

Periurethral injection of ASC improved urinary function and urethral structure in SUI rats

 Investigated whether transplantation of ASC

can treat SUI

Rats/ VD

1 × 106 rat ASC/ Urethral injections or IV [232]

↑ LPP,

↑ Sm-M

Transplantation of ASC was effective in the treatment and/or prevention of SUI

Anal sphincter

 Determined whether the injection of MDC into the anal sphincter can improve functional properties in a fecal incontinence model

Rats/ cryoinjured anal sphincter

3 × 106 rat MDC/ IM [79]

↑Ske-M, ↑Sm-M

Implanted autologous MDC improved anal sphincter function

 Investigated the ability of injected BMSC to enhance sphincter healing after injury and primary repair in vivo

Rats/ SP

0.75 × 106 rat BMSC/ IM [233]

↑Ske-M, ↑Sm-M,

↑contract

BMSC injection improved muscle regeneration and increased contractile function of anal sphincters

 Investigated the ability of rabbit BMSC/ human UCMSC to improve anal sphincter incontinence

Rabbits/ SP

104 rabbit BMSC/ human UCMSC/ IM [78]

↑ Ske-M, ↑contract

Stem cell injection at the site of injury enhanced contractile function of the anal sphincter without surgical repair

 Estimated the effect of myogenic stem cells on contractile function of the external anal sphincter after transection

Rats/ SP

3.2 × 106 rat myogenic stem cells/ IM [234]

↑Contract

Addition of myogenic stem cells improved function of the external anal sphincter after mechanical injury

 Determined possible mechanisms by which BMSC exert their regenerative potential to injured anal sphincter

Rats/ SP

4 × 106 rat BMSC/ IV; IM [235]

↑ contract, ↑ collagen deposition

Direct, but not IV, injection of BMSC into the injured anal sphincter improved contractile function of the sphincter, increased matrix deposition in the external anal sphincter after injury

 Evaluated in vivo function of the external anal sphincter after transection and repair augmented with myogenic stem cells

Rats/ SP

5 × 106 Rat myogenic stem cells/ IM [236]

↑ Anal pressure

Restoration of anal sphincter function by the transplantation of myogenic stem cells and associated trophic factors

 Evaluated functional recovery of injured anal sphincter after treatment with BMSC

Rats/ SP

or PNC

2 × 106 rat BMSC/ IV; IM [237]

↑ Anal pressure (SP)

BMSC treatment resulted in significant improvement in anal pressures after SP but not after PNC

 Evaluated the effect of myogenic stem cells on histological properties and the volume of striated muscle of the external anal sphincter after transection and repair

Rats/ SP

3.2 × 106 rat myogenic stem cells/ IM [238]

↑ Contract

Application of myogenic stem cells to transected/

repaired anal sphincters did not alter the amount of inflammation nor the volume of striated muscle but improved contractile function

 Evaluated the effect of MSC-laden hydrogel scaffold on contractile function and histomorphology of the external anal sphincter after transection injury

Rats/ SP

3.2 × 106 rat MSC (in hydrogel)/ IM [239]

↑ Ske-M, ↑ contract

A biologically compatible matrix facilitated stem cell survival, differentiation, or function leading to recovery of contractile function even after persistent disruption

 Investigated whether unexpanded BMNC are effective as in vitro expanded BMSC to enhance sphincter healing after injury and primary repair

Rats/ SP

3 × 106 rat BMSC: 7.38 × 106 rat BMNC/ IM [115]

↑ Sm-M, ↑ contract

Minimally manipulated BMSC were as effective as in vitro expanded BMSC for the recovery of anal sphincter injury followed by primary sphincter repair

 Assess the effects of co-application of laser and ASC on anal sphincter recovery after injury

Rabbits/ SP

2 × 106 human ASC/ IM [80]

↑ Anal pressure, ↑ Ske-M, ↑ Vas

Combination of laser and ASC were more effective than either treatment alone for promoting myogenesis, angiogenesis, and functional recovery

Lower esophageal sphincter

 Investigated whether transplantation of MDC into gastrointestinal sphincters improve their function

Rats/ Dogs

0.2 × 106 rat MDC; 4 × 106 dog MDC/ IM [106]

Rats:

↑ contract

Dogs:

↑ LES pressure, ↓ acid reflux

MDC survived and integrated into gastrointestinal smooth muscle and augmented their contractile response in two LES injury animal models

 Determined the role of autologous BMSC in the regeneration of the LES after surgery

Rats with esophagogastric myotomy

1.5 × 106 rat BMSC/ IM [116]

↑ Sm-M, ↑ contract

Use of BMSC improved sphincter regeneration of LES and control gastro-esophageal reflux after surgery