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Cotransplantation with specific populations of spina bifida bone marrow stem/progenitor cells enhances urinary bladder regeneration.

ABSTRACT: Spina bifida (SB) patients afflicted with myelomeningocele typically possess a neurogenic urinary bladder and exhibit varying degrees of bladder dysfunction. Although surgical intervention in the form of enterocystoplasty is the current standard of care in which to remedy the neurogenic bladder, it is still a stop-gap measure and is associated with many complications due to the use of bowel as a source of replacement tissue. Contemporary bladder tissue engineering strategies lack the ability to reform bladder smooth muscle, vasculature, and promote peripheral nerve tissue growth when using autologous populations of cells. Within the context of this study, we demonstrate the role of two specific populations of bone marrow (BM) stem/progenitor cells used in combination with a synthetic elastomeric scaffold that provides a unique and alternative means to current bladder regeneration approaches. In vitro differentiation, gene expression, and proliferation are similar among donor mesenchymal stem cells (MSCs), whereas poly(1,8-octanediol-cocitrate) scaffolds seeded with SB BM MSCs perform analogously to control counterparts with regard to bladder smooth muscle wall formation in vivo. SB CD34(+) hematopoietic stem/progenitor cells cotransplanted with donor-matched MSCs cause a dramatic increase in tissue vascularization as well as an induction of peripheral nerve growth in grafted areas compared with samples not seeded with hematopoietic stem/progenitor cells. Finally, MSC/CD34(+) grafts provided the impetus for rapid urothelium regeneration. Data suggest that autologous BM stem/progenitor cells may be used as alternate, nonpathogenic cell sources for SB patient-specific bladder tissue regeneration in lieu of current enterocystoplasty procedures and have implications for other bladder regenerative therapies.

SUBMITTER: Sharma AK

PROVIDER: S-EPMC3593834 | biostudies-other | 2013 Mar

REPOSITORIES: biostudies-other

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Cotransplantation with specific populations of spina bifida bone marrow stem/progenitor cells enhances urinary bladder regeneration.

Sharma Arun K AK Bury Matthew I MI Fuller Natalie J NJ Marks Andrew J AJ Kollhoff David M DM Rao Manoj V MV Hota Partha V PV Matoka Derek J DJ Edassery Seby L SL Thaker Hatim H Sarwark John F JF Janicki Joseph A JA Ameer Guillermo A GA Cheng Earl Y EY

Proceedings of the National Academy of Sciences of the United States of America 20130219 10

Spina bifida (SB) patients afflicted with myelomeningocele typically possess a neurogenic urinary bladder and exhibit varying degrees of bladder dysfunction. Although surgical intervention in the form of enterocystoplasty is the current standard of care in which to remedy the neurogenic bladder, it is still a stop-gap measure and is associated with many complications due to the use of bowel as a source of replacement tissue. Contemporary bladder tissue engineering strategies lack the ability to ...[more]

PMID: 23431178

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Project description:Complications associated with urinary bladder augmentation provide the motivation to delineate alternative bladder tissue regenerative engineering strategies. We describe the results of varying the proportion of bone marrow (BM) mesenchymal stem cells (MSCs) to CD34 + hematopoietic stem/progenitor cells (HSPCs) co-seeded onto synthetic POC [poly(1,8 octamethylene citrate)] or small intestinal submucosa (SIS) scaffolds and their contribution to bladder tissue regeneration. Human BM MSCs and CD34 + HSPCs were co-seeded onto POC or SIS scaffolds at cell ratios of 50 K CD34 + HSPCs/15 K MSCs (CD34-50/MSC15); 50 K CD34 + HSPCs/30 K MSCs (CD34-50/MSC30); 100 K CD34 + HSPCs/15 K MSCs (CD34-100/MSC15); and 100 K CD34 + HSPCs/30 K MSCs (CD34-100/MSC30), in male (M/POC; M/SIS; n = 6/cell seeded scaffold) and female (F/POC; F/SIS; n = 6/cell seeded scaffold) nude rats (n = 96 total animals). Explanted scaffold/composite augmented bladder tissue underwent quantitative morphometrics following histological staining taking into account the presence (S+) or absence (S-) of bladder stones. Urodynamic studies were also performed. Regarding regenerated tissue vascularization, an upward shift was detected for some higher seeded density groups including the CD34-100/MSC30 groups [F/POC S- CD34-100/MSC30 230.5 ± 12.4; F/POC S+ CD34-100/MSC30 245.6 ± 23.4; F/SIS S+ CD34-100/MSC30 278.1; F/SIS S- CD34-100/MSC30 187.4 ± 8.1; (vessels/mm2)]. Similarly, a potential trend toward increased levels of percent muscle (≥ 45% muscle) with higher seeding densities was observed for F/POC S- [CD34-50/MSC30 48.8 ± 2.2; CD34-100/MSC15 53.9 ± 2.8; CD34-100/MSC30 50.7 ± 1.7] and for F/SIS S- [CD34-100/MSC15 47.1 ± 1.6; CD34-100/MSC30 51.2 ± 2.3]. As a potential trend, higher MSC/CD34 + HSPCs cell seeding densities generally tended to increase levels of tissue vascularization and aided with bladder muscle growth. Data suggest that increasing cell seeding density has the potential to enhance bladder tissue regeneration in our model.

Project description:To date, there are no efficacious translational solutions for end-stage urinary bladder dysfunction. Current surgical strategies including urinary diversion and bladder augmentation enterocystoplasty (BAE) utilize autologous intestinal segments (e.g. ileum) to increase bladder capacity to protect renal function. Considered the standard of care, BAE is fraught with numerous short- and long-term clinical complications. Previous clinical trials employing tissue engineering approaches for bladder tissue regeneration have also been unable to translate bench-top findings into clinical practice. Major obstacles still persist which need to be overcome in order to advance tissue engineered products into the clinical arena. These include scaffold/bladder incongruencies, the acquisition and utlity of appropriate cells for anatomic and physiologic tissue recapitulation, and the choice of appropriate animal model for testing. Here we demonstrate that the elastomeric, bladder biomechanocompatible poly(1,8-octamethylene-citrate-co-octanol) (PRS; synthetic) scaffold co-seeded with autologous bone marrow-derived mesenchymal stem cells (MSCs) and CD34+ hematopoietic stem/progenitor cells (HSPCs) supports robust long-term, functional bladder tissue regeneration within the context of a clinically relevant baboon bladder augmentation model simulating bladder trauma. Partially cystectomized baboons were independently augmented with either autologous ileum or stem cell-seeded small intestinal submucosa (SIS; a commercially available biological scaffold) or PRS grafts. Stem cell synergism promoted functional tri-layer bladder tissue regeneration including whole graft neurovascularization in both cell-seeded grafts. However, PRS-augmented animals demonstrated fewer clinical complications and more advantageous tissue characterization metrics compared to ileum and SIS-augmented animals. Two-year study data demonstrate that PRS/stem cell-seeded grafts drive bladder tissue regeneration and are a suitable alternative to BAE.

Dataset Information

Cotransplantation with specific populations of spina bifida bone marrow stem/progenitor cells enhances urinary bladder regeneration.

Publications

Cotransplantation with specific populations of spina bifida bone marrow stem/progenitor cells enhances urinary bladder regeneration.

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