Markus Renninger

Generation of pluripotent stem cells from adult human testis

Human primordial germ cells and mouse neonatal and adult germline stem cells are pluripotent and show similar properties to embryonic stem cells. Here we report the successful establishment of human adult germline stem cells derived from spermatogonial cells of adult human testis. Cellular and molecular characterization of these cells revealed many similarities to human embryonic stem cells, and the germline stem cells produced teratomas after transplantation into immunodeficient mice. The human adult germline stem cells differentiated into various types of somatic cells of all three germ layers when grown under conditions used to induce the differentiation of human embryonic stem cells. We conclude that the generation of human adult germline stem cells from testicular biopsies may provide simple and non-controversial access to individual cell-based therapy without the ethical and immunological problems associated with human embryonic stem cells.

Development of a new outcome prediction model in carcinoma invading the bladder based on preoperative serum C‐reactive protein and standard pathological risk factors: the TNR‐C score

Study Type – Prognosis (case series)

A new prognostic model for cancer-specific survival after radical cystectomy including pretreatment thrombocytosis and standard pathological risk factors

Study Type – Prognosis (cohort series)

Stem cell therapy for voiding and erectile dysfunction.

Voiding dysfunction comprises a variety of disorders, including stress urinary incontinence and overactive bladder, and affects millions of men and women worldwide. Erectile dysfunction (ED) also decreases quality of life for millions of men, as well as for their partners. Advanced age and diabetes are common comorbidities that can exacerbate and negatively impact upon the development of these disorders. Therapies that target the pathophysiology of these conditions to halt progression are not currently available. However, stem cell therapy could fill this therapeutic void. Stem cells can reduce inflammation, prevent fibrosis, promote angiogenesis, recruit endogenous progenitor cells, and differentiate to replace damaged cells. Adult multipotent stem cell therapy, in particular, has shown promise in case reports and preclinical animal studies. Stem cells also have a role in urological tissue engineering for ex vivo construction of bladder wall and urethral tissue (using a patients own cells) prior to transplantation. More recent studies have focused on bioactive factor secretion and homing of stem cells. In the future, clinicians are likely to utilize allogeneic stem cell sources, intravenous systemic delivery, and ex vivo cell enhancement to treat voiding dysfunction and ED.

Differential Gene Expression Profiling of Enriched Human Spermatogonia after Short- and Long-Term Culture

This study aimed to provide a molecular signature for enriched adult human stem/progenitor spermatogonia during short-term (<2 weeks) and long-term culture (up to more than 14 months) in comparison to human testicular fibroblasts and human embryonic stem cells. Human spermatogonia were isolated by CD49f magnetic activated cell sorting and collagen−/laminin+ matrix binding from primary testis cultures obtained from ten adult men. For transcriptomic analysis, single spermatogonia-like cells were collected based on their morphology and dimensions using a micromanipulation system from the enriched germ cell cultures. Immunocytochemical, RT-PCR and microarray analyses revealed that the analyzed populations of cells were distinct at the molecular level. The germ- and pluripotency-associated genes and genes of differentiation/spermatogenesis pathway were highly expressed in enriched short-term cultured spermatogonia. After long-term culture, a proportion of cells retained and aggravated the “spermatogonial” gene expression profile with the expression of germ and pluripotency-associated genes, while in the majority of long-term cultured cells this molecular profile, typical for the differentiation pathway, was reduced and more genes related to the extracellular matrix production and attachment were expressed. The approach we provide here to study the molecular status of in vitro cultured spermatogonia may be important to optimize the culture conditions and to evaluate the germ cell plasticity in the future.

Evolution of the concept of androgen-sensitive bladder cancer

Abstract This reviews describes the concept of androgen-dependent growth of bladder cancer and the role of single-nucleotide polymorphisms (SNPs) located on chromosome 8q24 as a common carcinogenetic pathway for the development of concomitant prostate and bladder cancer. Recent genome-wide association studies have identified high-risk SNPs on chromosome 8q24 that have been linked with increased susceptibility for bladder and prostate cancer and alterations in the androgen receptor (AR) pathway. Muscle-invasive bladder cancers overexpress the AR, whereas in locally advanced or lymph-node positive stages loss of AR expression has been found. The prostate stem cell antigen (PSCA) gene possesses an androgen-responsive element (ARE) in its promoter region. Heterozymous and homozygous carriers of the SNP rs22940008 in the first exon of the PSCA gene are at increased risk for invasive bladder cancers. They exhibit significantly lower PSCA messenger RNA expression than patients with the wild-type genotype. Loss of the AR responsivity of the PSCA promoter may be a result of an altered affinity of the AR to the ARE mediated by the rs2294008 SNP or reduced expression of AR coactivators. Thereafter, induction of an androgen-independent mechanism, i.e. the insulin-like growth factor binding protein-2 signalling pathway – a key event in the development of hormone-independent prostate cancer – may increase tumour aggressiveness and metastatic potential of invasive bladder cancer cells. Loss of PSCA expression may represent an important step for androgen-independent growth, linked with the presence of the rs2294008 SNP. Determination of the AR status in cystectomy specimens offers new therapeutic approaches in locally advanced bladder cancer.

From tissue engineering to regenerative medicine in urology — The potential and the pitfalls ☆

Tissue engineering is a promising technique for the development of biological substitutes that can restore, maintain, or improve tissue function. The creation of human tissue-engineered products, generated of autologous somatic cells or adult stem cells with or without seeding of biocompatible matrices is a vision to resolve the lack of tissues and organs for transplantation and to offer new options for reconstructive surgery. Tissue engineering in urology aims at the reconstruction of the urinary tract by creating anatomically and functionally equal tissue. It is a rapidly evolving field in basic research and the transfer into the clinic has yet to be realized. Necessary steps from bench to bed are the proof of principle in animal models and the proof of concept in clinical trials following good manufacturing practice and ethical and legal requirements for human tissue-engineered products. Up to now, obstacles still occur in the neovascularization of implants and ingrowth of nerves in vivo. Moreover the harvesting of mesenchymal stem cells out of bone marrow as well as the explant of urothelial cells yet demands rather invasive surgery to achieve a successful outcome. Thus, other cell sources and harvesting techniques like placenta and adipose tissue for mesenchymal stem cells and bladder irrigation for urothelial cells require closer investigation.

Comparison of the new American Joint Committee on Cancer substratification in node-negative pT2 urothelial carcinoma of the bladder: analysis of patient outcomes in a contemporary series

Study Type – Prognosis (case series) Level of Evidence 4

Do we use the right criteria for determining the clinical significance of incidental prostate cancer at radical cystoprostatectomy

Abstract Prostate-sparing techniques have been advocated to improved functional outcomes after radical cystoprostatectomy (RCP) for invasive bladder cancer, but this may endanger the oncological outcome. This review addresses the current status of risk factors of prostate cancer (PCa) recurrence in patients with incidental PCa after RCP. The overall 7-year risk of PCa recurrence after RCP is approximately 9%. Increased risk has been suggested in the presence of clinically significant PCa as: ≥pT3a stage, presence of lymph-node metastasis, positive surgical margins, Gleason pattern ≥4, tumour multifocality (three or more foci) and tumour volume >0.5 cm3. However, the prognostic significance of these parameters has not been evaluated within multivariable analyses so far. Preoperatively elevated prostate-specific antigen (PSA) values correlate weakly with the clinical significance of incidental PCa, while prostate biopsy has a limited accuracy for detecting incidental PCa in the preoperative setting. Genetic markers, e.g. the prostate stem cell antigen (PSCA) gene, have recently been associated with risk of recurrence in patients with incidental PCa. Incidental PCa at RCP is usually clinically insignificant. Yet, clinicopathological parameters for clinical significant cancers have not been investigated independently in the literature so far. Consequently, lifelong PSA surveillance should be conducted in all patients with incidental PCa after RCP. In the presence of clinically significant PCa treatment decisions should be based not only on histological criteria but also on patient-centred parameters (e.g. patient age and comorbidities). Assessment of PSCA expression in RCP specimens may enable improved risk assessment for PCa recurrence after RCP.

Retraction: Generation of pluripotent stem cells from adult human testis

This corrects the article DOI: 10.1038/nature07404