Abstract
Consistency in clinical outcomes is key to the success of therapeutic Mesenchymal Stem/Stromal cells (MSCs) in regenerative medicine. MSCs are used to treat both humans and companion animals (horses, dogs, and cats). The properties of MSC preparations can vary significantly with factors including tissue of origin, donor age or health status. We studied the effects of developmental programming associated with intrauterine growth restriction (IUGR) on MSC properties, particularly related to multipotency. IUGR results from inadequate uterine capacity and placental insufficiency of multifactorial origin. Both companion animals (horses, dogs, cats) and livestock (pigs, sheep, cattle) can be affected by IUGR resulting in decreased body size and other associated changes that can include, alterations in musculoskeletal development and composition, and increased adiposity. Therefore, we hypothesized that this dysregulation occurs at the level of MSCs, with the cells from IUGR animals being more prone to differentiate into adipocytes and less to other lineages such as chondrocytes and osteocytes compared to those obtained from normal animals. IUGR has consequences on health and performance in adult life and in the case of farm animals, on meat quality. In humans, IUGR is linked to increased risk of metabolic (type 2 diabetes) and other diseases (cardiovascular), later in life. Here, we studied porcine MSCs where IUGR occurs spontaneously, and shows features that recapitulate human IUGR. We compared the properties of adipose-derived MSCs from IUGR (IUGR-MSCs) and Normal (Normal-MSCs) new-born pig littermates. Both MSC types grew clonally and expressed typical MSC markers (CD105, CD90, CD44) at similar levels. Importantly, tri-lineage differentiation capacity was significantly altered by IUGR. IUGR-MSCs had higher adipogenic capacity than Normal-MSCs as evidenced by higher adipocyte content and expression of the adipogenic transcripts, PPARγ and FABP4 (P < 0.05). A similar trend was observed for fibrogenesis, where, upon differentiation, IUGR-MSCs expressed significantly higher levels of COL1A1 (P < 0.03) than Normal-MSCs. In contrast, chondrogenic and osteogenic potential were decreased in IUGR-MSCs as shown by a smaller chondrocyte pellet and osteocyte staining, and lower expression of SOX9 (P < 0.05) and RUNX2 (P < 0.02), respectively. In conclusion, the regenerative potential of MSCs appears to be determined prenatally in IUGR and this should be taken into account when selecting cell donors in regenerative therapy programmes both in humans and companion animals.
Highlights
Mesenchymal Stem/Stromal cells (MSCs) are used in regenerative therapies both in humans [1] and in veterinary species [2,3,4,5,6]
Cells were cultured initially in Dulbecco’s Modified Eagle Medium (DMEM) High Glucose supplemented with 20% FBS (Life Technologies-Thermo Fisher Scientific) and 50 μg/ml basic fibroblast growth factor, and in the subsequent passages, bFGF was removed from the medium and FBS reduced to 10%
We sought to investigate the effects of fetal reprogramming on MSC properties in IUGR pigs
Summary
Mesenchymal Stem/Stromal cells (MSCs) are used in regenerative therapies both in humans [1] and in veterinary species (horses, dogs, and cats) [2,3,4,5,6]. MSCs are multipotent having the capacity of differentiating into cells of the mesenchymal lineage (adipocytes, osteocytes, and chondrocytes), and these features have been explored for regenerative therapeutic purposes. These cells produce trophic factors which are relevant to the repair processes in vivo, and are considered as “Medicinal Signaling Cells” [10]. Different factors, such as donor [11] and age [12], can have considerable impact on MSC properties and clinical outcome, increasing the difficulty of MSC standardization, commercialization and therapeutic use. Donor disease, such as diabetes and osteoarthritis [13, 14] can have a detrimental impact on the quality of MSC preparations from the stromal vascular fraction, which are heterogeneous cells obtained from extracts containing stem and other cells, such as those of endothelial and hematopoietic origin
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