Purpose: Using various nonphysiological tissue injury/repair models numerous studies have demonstrated the capacity of bone marrow derived cells to contribute to the repopulation of epithelial tissues following damage. To investigate whether this phenomenon might also occur during periods of physiological tissue degeneration/regeneration we compared the ability of bone marrow derived cells to rejuvenate the prostate gland in mice that were castrated and then later treated with dihydrotestosterone vs mice with prostate epithelium that had been damaged by lytic virus infection. Materials and Methods: Using allogenic bone marrow grafts from female donor transgenic mice expressing green fluorescent protein transplanted into lethally irradiated males we were able to assess the contributions of bone marrow derived cells to recovery of the prostatic epithelium in 2 distinct systems, including 1) surgical castration followed 1 week later by dihydrotestosterone replacement and 2) intraprostatic viral injection. Eight to 10-week-old male C57/Bl6 mice were distributed among bone marrow donor→recipient/prostate injury groups, including 5 with C57/Bl6→C57/Bl6/no injury, 3 with green fluorescent protein→C57/Bl6/no injury, 3 with green fluorescent protein→C57/Bl6/vehicle injection, 4 with green fluorescent protein→C57/Bl6/virus injection and 3 each with green fluorescent protein→C57/Bl6/castration without and with dihydrotestosterone, respectively. Prostate tissues were harvested 3 weeks after dihydrotestosterone replacement or 14 days following intraprostatic viral injection. Prostate tissue immunofluorescence was performed with antibodies against the epithelial marker cytokeratin 5/8, the hematopoietic marker CD45 and green fluorescent protein. Results: Mice that sustained prostate injury from vaccinia virus infection with concomitant severe inflammation and glandular disruption showed evidence of bone marrow derived cell reconstitution of prostate epithelium, that is approximately 4% of all green fluorescent protein positive cells in the epithelial compartment 14 days after injury expressed cytokeratin 5/8, similar to the proportion of green fluorescent protein positive cells in the prostate that no longer expressed the hematopoietic marker CD45. When prostatic degeneration/regeneration was triggered by androgen deprivation and reintroduction, no green fluorescent protein positive prostate epithelial cells were detected. Conclusions: These findings are consistent with a requirement for inflammation associated architectural destruction for the bone marrow derived cell contribution to the regeneration of prostate epithelium.
Bibliographical noteFunding Information:
Supported by American Urological Association/American Urological Association Education and Research Scholars Program, Mouse Models of Human Cancer Consortium Grant UO1 CA84294, principal investigator C. A. Shen; University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School and National Institutes of Health Grant HL54330, principal investigator S. J. Sharkis.
- bone marrow