Abstract
Local tissue ischemia is a prime cause responsible for the massive cell death in tissue-engineered (TE) constructs observed postimplantation. To assess the impact of ischemia on the death of implanted human multipotent stromal cells (hMSCs), which have great potential for repairing damaged tissues, we hereby investigated the in vivo temporal and spatial fate of human Luc-GFP-labeled MSCs within fibrin gel/coral scaffolds subcutaneously implanted in nude mice. In vivo bioluminescence imaging monitoring and histological analyses of the constructs tested confirmed the irremediable death of hMSCs over 30 days postimplantation. The kinetics of expression of three hypoxic/ischemic markers (HIF-1α, LDH-A, and BNIP3) was also monitored. Our results provided evidence that hMSCs located within the core of implanted constructs died faster and predominantly and strongly expressed the aforementioned ischemic markers. In contrast, cells located in the outer regions of TE constructs were reperfused by neovascularization and were still viable (as evidenced by their ex-vivo proliferative potential) at day 15 postimplantation. These results support the explanation that in the central part of the constructs tested, death of hMSCs was due to ischemia, whereas in the periphery of these constructs, cell death was due to another mechanism that needs to be elucidated.
Highlights
Tissue engineering aims at regenerating functional tissues by combining cells with a supporting substrate
To assess the impact of ischemia on the death of implanted human multipotent stromal cells, which have great potential for repairing damaged tissues, we hereby investigated the in vivo temporal and spatial fate of human Luc-GFP-labeled MSCs within fibrin gel/coral scaffolds subcutaneously implanted in nude mice
Local tissue ischemia is considered a prime cause for such accelerated cell mortality but it has never been clearly demonstrated in TE constructs so far
Summary
Tissue engineering aims at regenerating functional tissues by combining cells with a supporting substrate. MSCs encounter an ischemic environment of low oxygen tension and nutrient deprivation that could lead to their massive death in situ.[15] information regarding the cellular responses to the ischemic stress is crucially lacking in the tissue engineering field. For these reasons, the aim of the present study was to assess the impact of ischemia on the loss of hMSCs implanted in vivo. Because the intensity of the ischemic state that individual cells face varies with both their location throughout the construct (especially their distance from blood capillaries) and the postimplantation time, we hereby investigated the in vivo hMSCs fate at different levels of depth within TE constructs and at early, mid-, and late postimplantation time points
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