Since 1980, Assisted Reproductive Technology (ART) has gained worldwide acceptance and Intracytoplasmic Sperm Injection (ICSI) has since aided couples with severe male factor infertility to achieve pregnancies. However these techniques rely on the production of male gametes (sperm or spermatids) to fertilize a partner's oocyte in vitro. For those patients unable to provide sperm or spermatid samples, no treatment options are available. Several factors contribute to a patients' infertility that may result in a loss of gamete formation. These include genetic factors, exposure to environmental and industrial toxicants, and medical interventions such as chemotherapies and immune suppressant treatments. In particular, there are number of male patients who are currently sterile after they received treatment for cancer during prepubertal development. For these patients, there are no cures for their infertility/sterilty and they are unable to conceive a child with their partner as an adult. However, in vitro gametogenesis from patient-specific stem cells represent one potential cure for these sterile patients. Our recent work outlined a novel approach for differentiating human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) into advanced spermatogenic lineages including haploid spermatids with correct parent-of-origin genomic imprints on two loci. We have recently observed similar results with rhesus non-human primate ESCs (nhpESCs), iPSCs (nhpiPSCs) and somatic cell nuclear transfer- derived ESCs (nhp NT-ESCs) (preliminary data). This proposal seeks to determine whether haploid spermatids derived from rhesus induced pluripotent stem cells are capable of fertilizing a rhesus oocyte and developing to the blastocyst stage in vitro. If successful, this proposal would show that functional male gametes can be derived from no greater starting material than a skin biopsy. Furthermore, this proposal applies to PAR-13-115 Improvement of Animal Models for Stem Cell-based Regenerative Medicine (R21) because a) it will determine whether non-human primate pluripotent stem cells function similarly to human pluripotent stem cells in germ cell differentiation potential b) will develop a new technology by which germline cells derived from non-human primate pluripotent stem cells could potentially be used for examination of disease-specific alterations in DNA that could be passed on to the next generation and c) provide an animal stem-cell based model to treat male factor infertility. If successful, this work would enable research into using geneticall engineered non-human primate pluripotent stem cells for particular diseases to generate functional gametes to track transgenerational effects of disease mutations through the male germline.

Public Health Relevance

Medical treatments such as chemotherapies, exposure to environmental and industrial toxicants, and injury have all been shown to cause male factor infertility resulting in complete loss of sperm production. To date, there are no cures to enable these patients to conceive a child with their partner. Using non-human primates, this proposal seeks to develop a novel methodology by which functional gametes can be generated by induced pluripotent stem cells which are capable of fertilizing an oocyte.

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-CB-J (55))
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Mirochnitchenko, Oleg
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Emory University
Anatomy/Cell Biology
Schools of Medicine
United States
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