Stem cell therapy using autologous stem cells to treat degenerative diseases is promising; however, the limited availability and compromised quality of progenitor cells in aged and diseased patients limit its therapeutic potential. Alternatively, use of cord blood-derived stem cells is advantageous as it is easy to harvest, harmless to donor, ethical, ontogenetically primitive and can be stored in cord blood bank for years. Moreover, cord blood-derived stem cell transplantation is associated with reduced risk of developing graft versus host disease. However, from a single cord very limited number of stem cells could be isolated, which limits its clinical application. Our laboratory has developed a nanofiber-based ex-vivo human umbilical cord blood-derived stem cell expansion technology, which not only preserves stem cell characteristics also provides essential number of functional stem cells. Furthermore, we genetically modify nanofiber-expanded stem cells to enhance angiogenic/therapeutic potential for various degenerative diseases such as hind limb ischemia, myocardial ischemia, stroke-mediated ischemia, osteoporosis, Parkinson’s disease, and wound-healing. Current investigations use immunocompromised murine, rat and swine models for relevant studies. Molecular aspects of stem cell functionality are also being investigated in these animal models after cell-based therapy.