Bone Marrow Stem/Progenitor Cells Attenuate the Inflammatory Milieu Following Substitution Urethroplasty

Abstract

Substitution urethroplasty for the treatment of male stricture disease is often accompanied by subsequent tissue fibrosis and secondary stricture formation. Patients with pre-existing morbidities are often at increased risk of urethral stricture recurrence brought upon in-part by delayed vascularization accompanied by overactive inflammatory responses following surgery. Within the context of this study, we demonstrate the functional utility of a cell/scaffold composite graft comprised of human bone marrow-derived mesenchymal stem cells (MSC) combined with CD34+ hematopoietic stem/progenitor cells (HSPC) to modulate inflammation and wound healing in a rodent model of substitution urethroplasty. Composite grafts demonstrated potent anti-inflammatory effects with regards to tissue macrophage and neutrophil density following urethral tissue analyses. This was accompanied by a significant reduction in pro-inflammatory cytokines TNFα and IL-1β and further resulted in an earlier transition to tissue remodeling and maturation with a shift in collagen type III to I. Grafted animals demonstrated a progressive maturation and increase in vessel size compared to control animals. Overall, MSC/CD34+ HSPC composite grafts reduce inflammation, enhance an earlier transition to wound remodeling and maturation concurrently increasing neovascularization in the periurethral tissue. We demonstrate the feasibility and efficacy of a stem cell-seeded synthetic graft in a rodent substitution urethroplasty model.

Concise Review: Modulating Cancer Immunity with Hematopoietic Stem and Progenitor Cells

“…In a more nuanced role, HSPCs can enhance or diminish the highly educated adaptive immune system through MDSC‐like immune suppression or myeloid antigen‐presenting cell‐like immune activation . In each of these functions, HSPCs can enable or prevent infections, autoimmunity, cancers, and even modulate surgical site healing responses .…”

“…Hematopoietic stem and progenitor cells (HSPCs) at various stages of multipotency and lineagecommitment have been implicated as key modulators of immunity [1]. Namely, it has been suggested that HSPCs can regulate cancer progression [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17], drive autoimmunity [18][19][20], and regulate infections and inflammation [1,[20][21][22][23][24][25][26][27][28][29][30]. In each of these disease settings, multiple reports have described HSPC-mediated immune-suppressive and stimulatory functions.…”

Overview of Urethral Reconstruction by Tissue Engineering: Current Strategies, Clinical Status and Future Direction

“…It was also shown that bone marrowderived mesenchymal stem cells in combination with CD34 ? hematopoietic stem/progenitor cells can offer inflammatory modulation, increase vascularization and improve wound healing by reduction of collagen III:I production [23]. However, adipose derived stem cells (ASCs), seem be superior over other cell sources [1].…”

miR‐21 modification enhances the performance of adipose tissue‐derived mesenchymal stem cells for counteracting urethral stricture formation

“…Recently various strategies, including growth factors administration, gene therapy, and stem cell transplantation, have been used to improve the treatment of urethral stricture . Among these, the transplantation of mesenchymal stem cells (MSC)—the multipotent stromal progenitor cells—has been proved to enhance the tissue repair process and resulted in better performance . Large number of papers indicated that both multi‐potential ability to differentiate into specialized cells for injury replacement and its paracrine effects to regulate the wound healing process, contribute to high therapeutic potential of MSCs during tissue repair or regeneration process .…”

“…4,[7][8][9] Among these, the transplantation of mesenchymal stem cells (MSC)-the multipotent stromal progenitor cells-has been proved to enhance the tissue repair process and resulted in better performance. 10,11 Large number of papers indicated that both multi-potential ability to differentiate into specialized cells for injury replacement and its paracrine effects to regulate the wound healing process, contribute to high therapeutic potential of MSCs during tissue repair or regeneration process. [7][8][9] However, because of the unfavourable microenvironment in the repair site, such as inflammation and over-production of ROS induced oxidative stress, the poor viability of MSC at the transplanted site might significantly decreased its therapeutic potential performance.…”