A new generation of implantable constructs: developing implants that make of the endogenous responses and of the host body respectively the effectors and the bioreactor of tissue regeneration
Massimiliano Gaetani1,2,3,4, Roberta Tasso1,2,3,4, Ranieri Cancedda1,2,3,4, Pier Giulio Conaldi1,2,3,4
1Ri.MED Foundation, Palermo, Italy; 2Regenerative Medicine and Biomedical Technologies Unit, ISMETT, Palermo, Italy; 3Department of Oncology, Biology, and Genetics, University of Genoa, Genoa, Italy; 4A.O.U. San Martino - IST (National Cancer Research Institute), Genoa, Italy
Tissue engineering (TE) makes combined use of cells and biomaterials, as scaffolds, in order to restore tissue structure and function mostly thorugh the specific commitment of the implanted cells. Similarly to regenerative medicine and to therapies of immune-related disorders, TE holds many expectations from the use of mesenchymal stem cells (MSCs). For their properties of self-renewal, multipotency, immune system modulation and support for tissue repair and angiogenesis, MSCs are a major current focus of many academic, industrial and clinical interests.
Although MSCs can differentiate into various mesenchymal lineages and even trans-differentiate in culture, when successfully implanted in vivo, the new tissue is never of donor origin nor is justified by the incidence of differentiation of grafted MSCs. Within all human organs and tissues from which they are derived, MSCs are perivascular progenitors and regulate tissue homeostasis, repair and regeneration, leading to recruitment of macrophages, endothelial precursors and host pluripotent cells .
We recently showed that ectopic implants, in mice, of osteo-conductive scaffolds seeded with bone marrow (BM)-MCSs leaded to endochondral bone formation only when previously enriched in culture for early progenitors. These MSCs triggered regeneration by secreting bioactive molecules and so modulating the host microenvironment rather than directly differentiating into the injured tissue . Furthermore, like the ability to be enrolled in a specific commitment, the secretion of factors by MSC was shown to be dependent on cell progenitor state, and this activity is likely to be the most important for MSCs therapeutic potential. However, although it is known that MSCs orchestrate regeneration acting as “drugstores”, by secreting a mix of factors that trigger endogenous cascades , TE is still based on cells potentially differentiating into the injured tissue and on scaffolds engineered for this goal. Contrarily, engineering products based on biomaterials, cells or their derivates that might bring the microenvironment modulations necessary to induce the host specific tissue regeneration in vivo, is poorly unexplored. Using mass spectrometry-based proteomics, we quantitatively identified the factors specifically secreted by early progenitor BM-MSCs. By deciphering the milieu of secreted proteins and by systems biology analysis we also identified the biological responses that MSCs can induce in vivo .
This strategy is currently under further development, in order to understand how to rule TE toward a new generation of implantable constructs not necessarily involving the engraftment of the implanted cells or not even using cells, but ideally being applied as pharmaceutical devices that, if implanted locally within a damaged tissue area, will trigger host regenerative processes, and use the endogenous cells as the effectors and the host body as the bioreactor.
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