Regenerative medicine in urology

doi:10.1053/j.sempedsurg.2014.05.002

Seminars in Pediatric Surgery

Volume 23, Issue 3, June 2014, Pages 106-111

https://doi.org/10.1053/j.sempedsurg.2014.05.002 Get rights and content

Abstract

Repair and reconstruction of damaged tissues and organs has been a major issue in the medical field. Regenerative medicine and tissue engineering, as rapid evolving technologies, may offer alternative treatments and hope for patients with serious defects and end-stage diseases. Most urologic diseases could benefit from the development of regenerative medicine and tissue engineering. This article discusses the role of cells and materials in regenerative medicine, as well as the status of current role of regenerative medicine for the generation of specific urologic organs.

Introduction

Repair and reconstruction of damaged tissues and organs has been a major issue in the medical field. Resection of lesion, Repair with autologous tissue, and Replacement with allografts are the three R׳s in traditional surgery. However, autologous transplantation is limited by donor site conditions and may cause secondary donor site injury. Allogeneic transplantation is limited by donor organ shortage and may lead to tissue rejection. Therefore, researchers have been studying how to Regenerate damaged tissues and organs with new techniques, which is the fourth “R” in the development of novel treatments. Regenerative medicine is the process of replacing or regenerating of human cells, tissues, or organs to restore or establish normal function.¹ It is a rapidly evolving field, which incorporates tissue engineering, cell biology, biochemistry, material science, and many other disciplines. In order to restore the function of diseased organs, there are generally three different methodical approaches: (1) cell-based therapy, with autologous or allogeneic stem cells obtained from a biopsy and expanded in vitro for clinical application; (2) implantation of biological or synthetic materials to assist and guide the repair process; and (3) implantation of matrices that are seeded with cells.

An increasing significance of regenerative medicine and tissue engineering is observed in urology. Almost every urologic tissue and organ is being studied, and some of them have made the translation into clinical application. In this article, we review the general concepts of regenerative medicine in urology, including cells, materials, and major achievements for specific urologic organs.

Section snippets

Cells

Endogenous primary cells are one of the ideal cell sources in regenerative medicine. The use of these cells would prevent tissue rejection and reduce inflammatory issues. Adult urothelial cells have many critical functions, such as barrier against urine toxicity and the expansion ability to adjust to volume changes of the bladder. On the other hand, smooth muscle cells play a key role in urination. Both types of cells have been successfully obtained from bladder biopsy.² Scaffolds seeded with

Biomaterials

Traditionally, biomaterials have been used as an extracellular matrix (ECM) to support the cells against in vivo forces and to provide physical adhesiveness. They can also be loaded with bioactive factors, such as growth factors and cytokines, to further support the cells. However, recent years have witnessed the growing understanding that ECM should also play an important role in regulating cell functions and behavior, including gene expression, proliferation, migration, differentiation, and

Kidney

The kidney is one of the most challenging organs to regenerate within a human body because of its complicated structure and function. Filtration function is the most important one of the kidney. It is achieved by a combination of extremely complicated vascular structures and various types of cells. Besides, endocrinal functions of the kidney, such as erythropoietin secretion, have to be restored when regenerating a kidney. To generate fully functional human kidneys, researchers must preserve

Summary

The field of regenerative medicine is developing rapidly, and many encouraging achievements have been made. Regenerative medicine has evolved from simple repair of the defects to developing fully functional organs with normal structures. Some novel theories and practices have subverted traditional medical concepts. On the other hand, the clinical application of regenerative medicine is still at an early stage. Although some engineered tissues have been used in clinic settings, none of them can

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En los últimos 20 años, los esfuerzos de científicos de todas las especialidades médicas se han dirigido hacia un nuevo objetivo. Se trata de la posibilidad de que el cuerpo regenere por sí mismo los tejidos y órganos enfermos con los estímulos artificiales adecuados o la construcción de nuevos órganos funcionales para sustituir los dañados. Este proceso conlleva la colaboración por parte de otras ciencias como la ingeniería de materiales, la medicina molecular, la biotecnología y la impresión tridimensional. En la denominada medicina regenerativa, los urólogos han desempeñado un papel especialmente activo. La búsqueda de los diferentes factores requeridos, como biomateriales adecuados y compatibles, células versátiles, técnicas adecuadas para construir tejidos, biomoléculas disponibles y el conocimiento de todo ello, minimizando los riesgos, son algunos de los objetivos y aproximaciones actuales. A pesar de los obstáculos, hay estudios in vitro e in vivo que ya han revelado opciones esperanzadoras. Repasaremos los avances relacionados con la vejiga, la uretra, el uréter y los riñones. Las dificultades como las cuestiones éticas, la inversión de tiempo y los altos costes, han sido algunos de los inconvenientes encontrados. Todavía se requieren más estudios para su aplicación clínica en la vida diaria.
In the last two decades, a new purpose has collected great efforts from scientists in all branches of medicine. It is about the possibility to make the body regenerate ill tissues and organs by itself with de right artificial stimuli or the construction of new functional organs to replace the damaged ones. This process comprises various interdisciplinary approaches to healthcare, such as tissue engineering, molecular medicine, biotechnology, and three-dimensional printing. Urologists have been remarkably active in this field of medicine called Regenerative Medicine. The searching of the different requirements like suitable and compatible biomaterials, versatile cells, adequate techniques to construct tissues, available biomolecules, and the knowledge of all these minimizing risks, are some of the aims and the approximations until now. Despite many obstacles, in vitro and in vivo studies are already showing encouraging options. We will review the advances related to the bladder, urethra, ureter, and kidneys. Difficulties such as ethical issues, time investment and high costs, have been some of the drawbacks encountered. Further studies are still required for its clinical application in daily life.
Intravital imaging and single cell transcriptomic analysis for engraftment of mesenchymal stem cells in an animal model of interstitial cystitis/bladder pain syndrome
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Although minimal tumorigenic potency of M-MSCs derived from hESCs was reported [4,19,21], safety concerns regarding the engrafted M-MSCs with high expression of CDK1 or FOS should be thoroughly investigated in a future study. MSCs are being investigated for the treatment of diverse diseases, and show promising outcomes from animal models and clinical trials [8,52–54]. To facilitate the translation of preclinical studies into clinical practice, the precise in vivo behaviors of the engrafted cells after transplantation should be analyzed regarding their biological properties.
Mesenchymal stem cell (MSC) therapy is a promising treatment for various intractable disorders including interstitial cystitis/bladder pain syndrome (IC/BPS). However, an analysis of fundamental characteristics driving in vivo behaviors of transplanted cells has not been performed, causing debates about rational use and efficacy of MSC therapy. Here, we implemented two-photon intravital imaging and single cell transcriptome analysis to evaluate the in vivo behaviors of engrafted multipotent MSCs (M-MSCs) derived from human embryonic stem cells (hESCs) in an acute IC/BPS animal model. Two-photon imaging analysis was performed to visualize the dynamic association between engrafted M-MSCs and bladder vasculature within live animals until 28 days after transplantation, demonstrating the progressive integration of transplanted M-MSCs into a perivascular-like structure. Single cell transcriptome analysis was performed in highly purified engrafted cells after a dual MACS−FACS sorting procedure and revealed expression changes in various pathways relating to pericyte cell adhesion and cellular stress. Particularly, FOS and cyclin dependent kinase-1 (CDK1) played a key role in modulating the migration, engraftment, and anti-inflammatory functions of M-MSCs, which determined their in vivo therapeutic potency. Collectively, this approach provides an overview of engrafted M-MSC behavior in vivo, which will advance our understanding of MSC therapeutic applications, efficacy, and safety.
Tissue Engineering of the Reproductive System
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Thanks to the advances in immunosuppressive medications, the demand for organ transplantation has constantly grown over the last 50 years, and currently far exceeds the supply of available organs, including the organs of the reproductive system. Surgical reconstruction of structural and functional deficiencies, even though effective is complex and depends on the availability of appropriate tissue. Research efforts over the last two decades have achieved tremendous progress in the tissue-engineering and reconstructive strategies for the organs of the human reproductive system. This article provides an overview of the current challenges and the key achievements in the field.
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Recently, therapeutic strategies for treatment of diseases have been developed based on cell transplantation which offer alternative choices for some severe disorders. Regenerative medicine has been developed to reconstruct and restore damaged organ function via cell therapy [47,49]. In contrast to chemical drugs or mechanical devices, cell therapy can facilitate the repair of tissues via natural biochemical processes within the organs.
Spermatogonial stem cells are unique cells that line the basal lamina of seminiferous tubules in the testis and have the potential of self-renewal and differentiation.
These cells pass on genetic information to the next generation via the process of spermatogenesis and have an important role in the maintenance of male fertility. Recent reports have shown the pluripotency characteristics of spermatogonial stem cells at the cellular and molecular level. These cells can convert into Embryonic stem like cells that exhibit similar phenotype with embryonic stem cells and the capacity to differentiate into all three germ layers: Ectoderm, endoderm and mesoderm.
These properties make spermatogonial stem cells an appropriate source for use in regenerative medicine.
Spermatogonial stem cells considered as an alternative and novel cell source that limits the technical and ethical problems accompanied with the other pluripotent stem cells. Patient-specific cell lineages without limitations of immunological rejection and specific auto transplantation are the beneficial’s associated with these cell population.
Also, cell therapy based on spermatogonial stem cells engraftment, promises for preservation of fertility and induces the reproductive potential in infertile patients.
Here, we discuss the applications of spermatogonial stem cells in regenerative medicine with focus on all important aspects, including: cell isolation, propagation, differentiation and especially cell transplantation.
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Regenerative medicine is the process of replacing or regenerating human cells, tissues, or organs with the goal of restoration of structure and function.38 There are in essence 3 different conceptual approaches for tissue engineering: autologous or allogeneic stem cells obtained from a biopsy and expanded in vitro, implantation of biological materials to assist tissue repair, and implantation of matrices that are seeded with stem cells.39 Several trials have shown the potential of tissue-engineered corpus cavernosum as an alternative for surgical total phallic reconstruction.40,41
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¹: These authors contributed equally to this paper.

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Regenerative medicine in urology

Abstract

Introduction

Section snippets

Cells

Biomaterials

Kidney

Summary

J Urol

Arthroscopy

Lancet

Lancet

Cell

Biomaterials

Eur Urol

Urology

J Pediatr Surg

Biomaterials

Am J Pathol

Kidney Int

J Urol

J Urol

Lancet

J Urol

Eur Urol

J Urol

Urology

Lancet

J Urol

Eur Urol

A brief definition of regenerative medicine

Regen Med

De novo reconstitution of a functional mammalian urinary bladder by tissue engineering

Nat Biotechnol

Phenotypic and functional characterization of in vivo tissue engineered smooth muscle from normal and pathological bladders

J Urol

Stem cells in regenerative medicine: introduction

Br Med Bull

Supralethal whole body irradiation and isologous marrow transplantation in man

J Clin Invest

Mesenchymal stem cells reside in virtually all post-natal organs and tissues

J Cell Sci

Embryonic stem cell lines derived from human blastocysts

Science

Stem cells. Setting standards for human embryonic stem cells

Science

All-trans retinoic acid directs urothelial specification of murine embryonic stem cells via GATA4/6 signaling mechanisms

PLoS One

Good manufacturing practice and clinical-grade human embryonic stem cell lines

Hum Mol Genet

Establishment and maintenance of human embryonic stem cell lines on human feeder cells derived from uterine endometrium under serum-free condition

Biol Reprod

Human adult marrow cells support prolonged expansion of human embryonic stem cells in culture

Stem Cells

The tumorigenicity of human embryonic and induced pluripotent stem cells

Nat Rev Cancer

Induced pluripotent stem cell lines derived from human somatic cells

Science