Marvin Meistrich, Ph.D.
Gunapala Shetty, Ph.D.
Areas of Research
- Male Reproductive Biology
- Germline Mutagenesis
- Radiation Therapy
- Stem Cell Biology
- Testicular Cancer
Research in the Meistrich/Shetty Laboratory.
Our research interests are focused on how cancer therapy, particularly radiation therapy and chemotherapy, affects the male reproductive system. This is an important issue for patients as sperm production is very sensitive to these agents resulting in prolonged or permanent azoospermia and infertility. In addition, if spermatogenesis recovers, there is concern as to whether the sperm produced are carrying newly induced mutations caused by these genotoxic therapies, which may produce genetic disease in their offspring.
Recently we have been most concerned about fertility preservation in young males. Whereas adult males can preserve their fertility by sperm banking before gonadotoxic therapy, prepubertal boys do not have that option. However, the spermatogonial stem cells in their testes have the capability of producing sperm in the proper environment. We have shown that spermatogonial stem cells harvested from prepubertal rhesus monkeys before gonadal irradiation can be transplanted back to the testes after puberty and develop to produce sperm capable of fertilization. In addition, we have shown that prepubertal testis tissue harvested from rhesus monkeys can be subsequently grafted back to the interior of the scrotal skin, and will produce spermatozoa that can be used for in vitro fertilization and give rise to a healthy baby monkey. We are currently further developing those techniques for application to human and the future fertility of young boys who have cryopreserved testicular tissue prior to their cancer therapy.
Our other approach to fertility preservation is to manipulate spermatogonial stem cell proliferation to enhance recovery of spermatogenesis after gonadotoxic cancer therapy. Fibroblast growth factor (FGF) as well as granulocyte colony stimulating factor (GCSF) can stimulate the proliferation of spermatogonial stem cells. By manipulating the levels and activity of these factors in vivo we propose to (1) increase the pool of spermatogonial stem cells before therapy, (2) place the cells in a non-proliferative state during therapy so that they will become more resistant and (3) enhance their proliferation after therapy so as to accelerate the recovery of spermatogenesis. We are initially testing these agents to protect spermatogenesis in mice undergoing chemo- and radiation-therapy, and subsequently propose to do the same in rhesus monkeys.
Sosa E, Chen D, Rojas EJ, Hennebold JD, Peters KA, Wu Z, Lam TN, Mitchell JM, Sukhwani M, Tailor RC, Meistrich ML, Orwig KE, Shetty G, Clark AT. Differentiation of primate primordial germ cell-like cells following transplantation into the adult gonadal niche. Nature Communications 9(1):5339, 2018. PMC6297357.
Maher GJ, Bernkopf M, Koelling N, Wilkie AOM, Meistrich ML, Goriely A. The impact of chemo- and radiotherapy treatments on selfish de novo FGFR2 mutations in sperm of cancer survivors. Hum Reprod 34:1404, 2019 PMC6688873
Fayomi AP, Peters K, Sukhwani M, Valli-Pulaski H, Shetty G, Meistrich ML, Houser L, Robertson N, Roberts V, Ramsey C, Hanna C, Hennebold JD, Dobrinski I, Orwig KE. Autologous grafting of cryopreserved prepubertal rhesus testis produces sperm and offspring. Science 363:1314, 2019. PMID 30898927.
Meistrich ML. Risks of Genetic Damage in Offspring Conceived Using Sperm Produced during Chemotherapy or Radiotherapy. Andrology 8:545. 2020, PMID: 31821745.
Shetty G, Mitchell JM, Meyer JM, Wu Z, Lam TN, Phan TT, Zhang J, Hill L, Tailor RC, Peters KA, Penedo MC, Hanna C, Orwig KE, Meistrich ML. Restoration of Functional Sperm Production in Irradiated Pubertal Rhesus Monkeys by Spermatogonial Stem Cell Transplantation. Andrology. 2020, doi: 10.1111/andr.12807. Online ahead of print. PMID: 32351003
Next Generation Therapies for Fertility Preservation in Male Cancer Patients
NIH/NICHD 1 R01 HD100197-01A1
Kyle Orwig and Marvin Meistrich, Co-PIs.
Project Direct Costs to MD Anderson/Year $300,683