Stem cell therapy for erectile dysfunction: a critical review

Abstract

Erectile dysfunction (ED) is a prevailing health problem that seriously impacts quality of life. Current treatment options are less effective for patients having cavernous nerve (CN) injury or diabetes mellitus-related ED. These 2 types of ED are thus the main focus of past and current stem cell (SC) therapy studies. In a total of 16 studies so far, rats were exclusively used as disease models and SCs were mostly derived from bone marrow, adipose tissue, or skeletal muscle. For tracking, SCs were labeled with LacZ, green fluorescent protein, 4',6-diamidino-2-phenylindole, DiI, bromodeoxyuridine, or 5-ethynyl-2-deoxyuridine, some of which might have led to data misinterpretation. SC transplantation was done exclusively by intracavernous (IC) injection, which has been recently shown to have systemic effects. Functional assessment was done exclusively by measuring increases of IC pressure during electrostimulation of CN. Histological assessment usually focused on endothelial, smooth muscle, and CN contents in the penis. In general, favorable outcomes have been obtained in all trials so far, although whether SCs had differentiated into specific cell lineages remains controversial. Recent studies have shown that intracavernously injected SCs rapidly escaped the penis and homed into bone marrow. This could perhaps explain why intracavernously injected SCs had systemic antidiabetic effects and prolonged anti-ED effects. These hypotheses and the differentiation-versus-paracrine debate require further investigation.

FIG. 1.

Penile histology of a normal rat. The cross-section of rat penis was stained with Alexa-488-conjugated phalloidin, which detects smooth muscle (green stain), with Alexa-594-conjugated anti-RECA antibody, which detects endothelium (red stain), and with DAPI, which detects cell nuclei (blue stain). DAPI, 4’,6-diamidino-2-phenylindole; CC, corpus cavernosum; Pha, phalloidin; RECA, rat endothelial cell antigen.

FIG. 2.

Histological changes in the penises of ED rats. Representative images from normal rats and indicated ED models illustrate ED-associated changes in smooth muscle (left column), endothelium (middle column), and nNOS-positive nerves (right column). Quantification of these changes in 9 rats in each group of rats was done as described in our previous studies, and the results are shown at the bottom. For smooth muscle and endothelium, the unit on the Y-axis is number of pixels/high-power field (HPF). For nNOS, the unit is number/HPF, where “number” refers to the red dots seen in the images. Note that all tissue sections were costained with DAPI for the visualization of cell nuclei (blue). ED, erectile dysfunction; nNOS, neuronal nitric oxide synthase.

FIG. 3.

A schematic representation of the experimental procedures of a typical preclinical stem cell therapy for ED. The donor rat and recipient rat can be the same (autologous) or different (allogeneic). The isolation and cultivation of SCs vary from one type to another. Modification and sorting of SCs are desired by some researchers, although a higher benefit versus risk ratio has not been demonstrated. Labeling of SCs, which is unnecessary if from a GFP donor rat, usually incorporates a chemical agent that can be later detected by color or fluorescence. Transplantation of the labeled SCs has so far been conducted universally by IC injection, as indicated with the cross-sectional view of the penis of an animal whose erectile function has been compromised by various means, for example, CN injury and streptozotocin injection. Weeks or months after SC transplantation, the animals are tested for erectile function, usually by measurement of increases in intracavernous pressure (ICP) during electrostimulation of CN. The animals are then sacrificed for histological assessment of corpus cavernosum and identification of the injected SCs. SCs, stem cells; GFP, green fluorescence protein; IC, intracavernous; CN, cavernous nerve.