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The effects of bone marrow stem and progenitor cell seeding on urinary bladder tissue regeneration.

ABSTRACT: 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.

SUBMITTER: Bury MI

PROVIDER: S-EPMC7840904 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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The effects of bone marrow stem and progenitor cell seeding on urinary bladder tissue regeneration.

Bury Matthew I MI Fuller Natalie J NJ Sturm Renea M RM Rabizadeh Rebecca R RR Nolan Bonnie G BG Barac Milica M Edassery Sonia S SS Chan Yvonne Y YY Sharma Arun K AK

Scientific reports 20210127 1

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 ...[more]

PMID: 33504876

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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.

Project description:Recent studies have demonstrated that mesenchymal stem cells (MSCs) combined with CD34+ hematopoietic/stem progenitor cells (HSPCs) can function as surrogate urinary bladder cells to synergistically promote multi-faceted bladder tissue regeneration. However, the molecular pathways governing these events are unknown. The pleiotropic effects of Wnt5a and Cyr61 are known to affect aspects of hematopoiesis, angiogenesis, and muscle and nerve regeneration. Within this study, the effects of Cyr61 and Wnt5a on bladder tissue regeneration were evaluated by grafting scaffolds containing modified human bone marrow derived MSCs. These cell lines were engineered to independently over-express Wnt5a or Cyr61, or to exhibit reduced expression of Cyr61 within the context of a nude rat bladder augmentation model. At 4 weeks post-surgery, data demonstrated increased vessel number (~250 vs ~109 vessels/mm2) and bladder smooth muscle content (~42% vs ~36%) in Cyr61OX (over-expressing) vs Cyr61KD (knock-down) groups. Muscle content decreased to ~25% at 10 weeks in Cyr61KD groups. Wnt5aOX resulted in high numbers of vessels and muscle content (~206 vessels/mm2 and ~51%, respectively) at 4 weeks. Over-expressing cell constructs resulted in peripheral nerve regeneration while Cyr61KD animals were devoid of peripheral nerve regeneration at 4 weeks. At 10 weeks post-grafting, peripheral nerve regeneration was at a minimal level for both Cyr61OX and Wnt5aOX cell lines. Blood vessel and bladder functionality were evident at both time-points in all animals. Results from this study indicate that MSC-based Cyr61OX and Wnt5aOX cell lines play pivotal roles with regards to increasing the levels of functional vasculature, influencing muscle regeneration, and the regeneration of peripheral nerves in a model of bladder augmentation. Wnt5aOX constructs closely approximated the outcomes previously observed with the co-transplantation of MSCs with CD34+ HSPCs and may be specifically targeted as an alternate means to achieve functional bladder regeneration.

Dataset Information

The effects of bone marrow stem and progenitor cell seeding on urinary bladder tissue regeneration.

Publications

The effects of bone marrow stem and progenitor cell seeding on urinary bladder tissue regeneration.

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