Reply to the Commentary on "New Frontiers or the Treatment of Interstitial Cystitis/Bladder Pain Syndrome-Focused on Stem Cells, Platelet-Rich Plasma, and Low-Energy Shock Wave".

To the editor,

We appreciate the authors’ comments on the new frontiers for the treatment of interstitial cystitis/bladder pain syndrome (IC/BPS) [1]. The authors highlighted the importance of safety concerns, therapeutic mechanisms, immunogenicity, the ability to cross biological barriers and cell death resulted from stem cells transplantation. Exosomes secreted by mesenchymal stem cells (MSCs) that are able to mediate the regenerative and anti-inflammatory effects in many pathological conditions have raised considerable interests as a cell-free therapeutic alternative.

The therapeutic effects of MSCs mediated partly through the paracrine release of various bioactive factors [1]. Some of the therapeutic effects are mediated by MSCs-derived extracellular vesicles (EVs), a generic term for a heterogeneous group of cellreleased membranous structures comprising endosome-origin “exosomes” and plasma membrane-derived “microvesicles” (microparticles/ectosomes) [2]. EVs are widely presented in biological fluid and could be produced by most types of cells , including mature cells, tumor cells, immune cells, and stem cells [3]. Due to most mature cells secreted very little EVs, at present, most studies focused on EVs derived from tumor cells, immune cells, and MSCs [4]. The contents of EVs, including proteins, lipids, and regulatory RNA, vary according to the external stimulation and the cell type that secreted them [5]. At present, most MSCs-derived EVs studies focused on exosomes, microvesicles and EVs derived from four main sources of MSCs, including bone marrow MSCs, human umbilical cord MSCs, adipose-derived MSCs, and human embryonic MSCs [3].

Adamowicz et al. [6] reported that MSCs-conditioned medium is abundant of regenerative and anti-inflammatory factors; therefore, the utilization of MSCs-conditioned medium as a cell-free therapy seems to be an ideal substance to prevent IC/BPS recurrence. Although the authors mention exosomes derived from MSCs avoid most of the above risks and retain similar therapeutic effects to their parental MSCs in many diseases, upon searching PubMed and www.clinicaltrials.gov using key words such as “interstitial cystitis,” “bladder pain syndrome,” “EVs,” “exosomes,” “microvesicles,” and so forth, we do not find any publications in literature review or clinical trials evaluate the effects of exosomes, microvesicles and/or EVs on IC/BPS in vitro and in vivo. This important issue must be addressed in the future studies.

Although a growing number of clinical trials of MSCs-derived EVs based therapy have made some progression in some disease, clinical translational researches still face many challenges. First the therapeutic mechanisms, optimal dose, adverse effects, durability of MSCs-EVs treatment effects are not clear. Questions also remain about lack of standardized manufacturing processes and methods, which need to be resolved in the future.