Abstract
It is currently controversially discussed whether mesenchymal stem cells (MSC) facilitate cartilage regeneration in vivo by a progenitor- or a nonprogenitor-mediated mechanism. Here, we describe a potentially novel unbiased in vivo cell tracking system based on transgenic donor and corresponding immunocompetent marker-tolerant recipient mouse and rat lines in inbred genetic backgrounds. Tolerance of recipients was achieved by transgenic expression of an immunologically neutral but physicochemically distinguishable variant of the marker human placental alkaline phosphatase (ALPP). In this dual transgenic system, donor lines ubiquitously express WT, heat-resistant ALPP protein, whereas recipient lines express a heat-labile ALPP mutant (ALPPE451G) resulting from a single amino acid substitution. Tolerance of recipient lines to ALPP-expressing cells and tissues was verified by skin transplantation. Using this model, we show that intraarticularly injected MSC contribute to regeneration of articular cartilage in full-thickness cartilage defects mainly via a nonprogenitor-mediated mechanism.
Highlights
Mesenchymal stem cells (MSC) are multipotent cells isolated from adult BM or other tissues
For our proof-of-principle experiments, we employed alkaline phosphatase (ALPP) as marker due to its ease of detection in soft [16,17,18] and hard tissues [19] and because ALPP is known to be developmentally neutral in mice and rats [16] and does not influence the behavior of ALPP-expressing MSC [20]
We present a potentially novel in vivo cell tracking system that allows the fate of ALPP-labeled cells and tissues in immunocompetent recipients to be followed over long periods of time in the complete absence of immune-mediated rejection
Summary
Mesenchymal stem cells (MSC) are multipotent cells isolated from adult BM or other tissues. Several studies investigating cartilage regeneration using intraarticularly injected MSC reported promising results in different model systems [2,3,4,5,6], it is currently controversially discussed whether the positive therapeutic effects of MSC are due to a progenitor or a nonprogenitor function of injected cells [7] It is unclear whether MSC injected into a joint attach to cartilage lesions, divide, differentiate, and give rise to new MSC-derived chondrocytes, or whether they just orchestrate regeneration by a nonprogenitor function, e.g., by secreting factors stimulating host cells to promote regeneration. We have recently shown that genetically labeled MSC are able to attach to cartilage lesions via a β1 integrin–mediated mechanism in vitro [8], but it is generally believed that, in vivo, only few of the intraarticularly injected cells adhere to damaged cartilage and may subsequently participate in tissue regeneration
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