Tiam Mana Saffari

243 GENERAL DISCUSSION 11 MSCs, presented in Chapter 9 . Undifferentiated MSCs delivered to the nerve allograft specifically, results in a significant increase in isometric tetanic force. How does the augmentation of nerve allografts with stem cells enhance motor recovery? I could hypothesize that stem cells improve a pro-tolerogenic cellular paracrine environment for nerve allografts, resulting in stimulation of neurotrophic and angiogenic growth factors, ultimately leading to enhanced motor recovery. Undifferentiated and differentiated MSCs each exert different interactions with the surrounding microenvironment leading to their individual stem cell secretome over time in vitro 40 . However, it remains unclear how the differences in interactions with the microenvironment may change in vivo over a period of months , as the finite survival of MSCs is described up to 29 days in rats 63 . It is believed that the growth factors, secreted by MSCs, stimulate neuroregenerative cascades which consecutively remain active past stem cell survival, resulting in motor outcome changes at 12 weeks. At 16 weeks, outcomes between all groups have been normalized, consistent with the well- known superlative nerve regenerative capacity of the rat 64 . After investigating the independent effects of (i) angiogenesis (Part I of the general discussion) and (ii) stem cells on nerve regeneration, these two have been combined to evaluate their effect on microvascular architecture of nerve allografts. In Chapter 10 , it was found that the combination of angiogenesis with undifferentiated MSCs resulted in the greatest increase of revascularization of nerve allografts compared to all experimental groups. Not only has this combined treatment led to the increase of quality (i.e. size and distribution) of vessels, but it has also regulated directionality of vessels resulting in reaching the mid-section of the nerve allograft. While angiogenesis combined with differentiated MSCs resulted in a mesh network of non-organized microvessels, longitudinally running vessels along the entire length of the nerve graft were found when undifferentiated MSCs were combined with angiogenesis. Although the interaction of angiogenesis and stem cells has not been investigated previously, these findings provide evidence for a novel interaction that may further enhance nerve regeneration. I hypothesize that the (i) increase in vascularity and (ii) supportive paracrine microenvironment, provided by stem cells and SIEF f lap, aid in diminishing fibrosis of the nerve graft, subsequently leading to enhanced nerve regeneration. This may be further supported by (iii) organized