Chemokine Therapy in Cats With Experimental Renal Fibrosis and in a Kidney Disease Pilot Study.

Background: Chronic tubulointerstitial fibrosis is a common final pathway leading to end stage kidney disease in cats and has no effective treatment. The use of cell-based molecules to treat kidney fibrosis may be a promising approach. The objectives were to test the effects of intra-renal chemokine CXCL12 injection in a pre-clinical cat model of unilateral ischemia/reperfusion (I/R)-induced kidney fibrosis and then, within a clinical pilot study, test the safety/feasibility of CXCL12 injection in cats that might have early chronic kidney disease (CKD). Methods: Pre-clinical: Thirty cats received intra-renal injection of 100, 200, or 400 ng of recombinant human CXCL12, or sterile saline, into the I/R kidney 70 days post-injury, or were non-injured, non-injected controls (n = 6/group). Kidney collagen content was quantified 4 months post-treatment using Masson's Trichrome and Picrosirius Red (PSR) stained tissues. In a separate study (n = 2) exploring short-term effects of CXCL12, 200 ng CXCL12 was injected into I/R kidneys and then harvested either 30 min (n = 1) or 1 month (n = 1) post-injection. Kidney concentrations of CXCL12, matrix metalloproteinase 1 (MMP-1), and lysyl oxidase-like enzyme 2 (LOXL-2) were quantified via ELISA. Clinical Pilot: 14 client-owned cats with potential early kidney disease received a single-treatment, bilateral intra-renal injection of 200 ng CXCL12 (n = 7), or received no injection (n = 7). Blood/urine samples were collected monthly for 9 months to assess renal function and CKD staging. Results: Pre-clinical: I/R increased the affected kidney collagen content, which both mid and high doses of CXCL12 restored to normal (ps < 0.05 vs. untreated). I/R increased collagen fiber width, which both mid and high doses of CXCL12 restored to normal (p < 0.001 vs. untreated). Early changes in kidney MMP-1, associated with collagen breakdown, and subsequent decreases in LOXL-2, associated with collagen cross-linking, in response to CXCL12 treatment may contribute to these findings. Clinical Pilot: Bilateral intra-renal injection of CXCL12 using ultrasound guidance in cats with CKD was feasible and safe in a general practice clinical setting with no obvious side effects noted during the 9-month follow-up period. Conclusions: Intra-renal injection of CXCL12 may prove to be an effective treatment for kidney fibrosis in cats with CKD. Additional mechanistic and clinical evaluations are needed.

Regenerative medicine for anal incontinence: a review of regenerative therapies beyond cells.

INTRODUCTION AND HYPOTHESIS: Current treatment modalities for anal sphincter injuries are ineffective for many patients, prompting research into restorative and regenerative therapies. Although cellular therapy with stem cells and progenitor cells show promise in animal models with short-term improvement, there are additional regenerative approaches that can augment or replace cellular therapies for anal sphincter injuries. The purpose of this article is to review the current knowledge of cellular therapies for anal sphincter injuries and discusses the use of other regenerative therapies including cytokine therapy with CXCL12. METHODS: A literature search was performed to search for articles on cellular therapy and cytokine therapy for anal sphincter injuries and anal incontinence. RESULTS: The article search identified 337 articles from which 33 articles were included. An additional 12 referenced articles were included as well as 23 articles providing background information. Cellular therapy has shown positive results for treating anal sphincter injuries and anal incontinence in vitro and in one clinical trial. However, cellular therapy has disadvantages such as the source and processing of stem cells and progenitor cells. CXCL12 does not have such issues while showing promising in vitro results for treating anal sphincter injuries. Additionally, electrical stimulation and extracorporeal shock wave therapy are potential regenerative medicine adjuncts for anal sphincter injuries. A vision for future research and clinical applications of regenerative medicine for anal sphincter deficiencies is provided. CONCLUSION: There are viable regenerative medicine therapies for anal sphincter injuries beyond cellular therapy. CXCL12 shows promise as a focus of therapeutic research in this field.

Applicability of regenerative medicine and tissue engineering for the treatment of stress urinary incontinence in female patients.

Stress urinary incontinence (SUI) is an age health-related issue that generates interest due to its considerable public health burden and the controversies surrounding treatment. It is highly prevalent affecting 30-40% of all women during their lifetime. Midurethral slings are the standard of gold standard treatment for female patients with SUI. They have excellent short-term cure rates; however, their efficacy tends to decrease over time and patients often report urinary incontinence recurrence. This paper addresses the applicability of regenerative medicine and tissue engineering for the treatment of SUI in female patients. Cell-based treatment with periurethral injection of autologous adipose or muscle-derived stem cells have been used for SUI; however, the cure rates and SUI recurrence at 1 year were 40% and 70%, respectively. Novel minimally invasive approaches, such as low-intensity extracorporeal shock wave therapies have shown promising results in SUI animal models. In addition, local injection of growth factors, chemokines, and specific antibodies have shown histological evidence of neoangiogenesis, nerve, and sphincter regeneration in rodents and nonhuman primates with SUI. The use of bioactive factors and proteins secreted by cells, which is called secretomes, have been recognized as key regulators of various mechanisms, such as immunomodulation, angiogenesis, inflammation, apoptosis, and tissue repair. Emerging therapies aiming to replace or restore tissues and organ functionality may improve the long-term efficacy and in the near future may represent the standard of care for the treatment of SUI.

New concepts in regenerative medicine approaches to the treatment of female stress urinary incontinence.

PURPOSE OF REVIEW: Update on recent regenerative medicine approaches to the treatment of stress urinary incontinence (SUI) caused by intrinsic sphincter deficiency (ISD). RECENT FINDINGS: In the treatment of female SUI/ISD, results using different types of cellular therapy have been disappointing, and new approaches are desirable. To advance our regenerative medicine approaches to SUI/ISD, it is critical to utilize animal models that best parallel the pathophysiology of this disease in women. Many current animal models mimic acute SUI/ISD. However, SUI/ISD in women is usually a chronic condition resulting from previous muscle and nerve sphincter damage during parturition or muscle loss during aging. Similar to women, a nonhuman primate (NHP) model of chronic SUI/ISD has demonstrated only modest response to cell therapy. However, treatment with stromal cell-derived factor 1 (SDF1), also known as C-X-C motif chemokine 12 (CXCL12) restored continence in this model. SUMMARY: As a potential therapeutic approach, the use of a well characterized chemokine, such as CXCL12, may by-pass the lengthy and expensive process of cell isolation, expansion, and injection. Recent findings in this new NHP model of chronic SUI/ISD may open up the field for noncell-based treatments.