Regulating activation of transplanted cells controls tissue regeneration

Abstract

Current approaches to tissue regeneration are limited by the death of most transplanted cells and͞or resultant poor integration of transplanted cells with host tissue. We hypothesized that transplanting progenitor cells within synthetic microenvironments that maintain viability, prevent terminal differentiation, and promote outward migration would significantly enhance their repopulation and regeneration of damaged host tissue. This hypothesis was addressed in the context of muscle regeneration by transplanting satellite cells to muscle laceration sites on a delivery vehicle releasing factors that induce cell activation and migration (hepatocyte growth factor and fibroblast growth factor 2) or transplantation on materials lacking factor release. Controls included direct cell injection into muscle, the implantation of blank scaffolds, and scaffolds releasing factors without cells. Injected cells demonstrated a limited repopulation of damaged muscle and led to a slight improvement in muscle regeneration, as expected. Delivery of cells on scaffolds that did not promote migration resulted in no improvement in muscle regeneration. Strikingly, delivery of cells on scaffolds that promoted myoblast activation and migration led to extensive repopulation of host muscle tissue and increased the regeneration of muscle fibers at the wound and the mass of the injured muscle. This previously undescribed strategy for cell transplantation significantly enhances muscle regeneration from transplanted cells and may be broadly applicable to the various tissues and organ systems in which provision and instruction of a cell population competent to participate in regeneration may be clinically useful.fibroblast growth factor 2 ͉ hepatocyte growth factor ͉ myoblast ͉ satellite cell ͉ tissue engineering

Engineering Musculoskeletal Tissues with Human Embryonic Germ Cell Derivatives

“…One of the drawbacks that limit the translation of successful in vitro approaches to in vivo is the death of transplanted cells [45]. Our in vivo results demonstrate the survival and continuous tissue formation of transplanted constructs.…”

Regenerative medicine in orthopaedic surgery

“…A variety of systems have been developed to encapsulate both recombinant growth factors and plasmid DNA encoding these factors in biodegradable polymer platforms useful for tissue engineering, 59,60 and these systems can be designed to enable combinations or sequences of factors to be delivered with well controlled kinetics, 61,62 which more closely mimics the normal developmental and regenerative processes than delivery of single factors. The utility of this approach has recently been demonstrated in the context of bone and muscle regeneration, 54,61,63 and in the formation of new blood vessel networks that can alleviate tissue ischemia and enhance the regenerative potential of cell transplantation strategies. 64 …”

“…51,53 While a large number of studies indicate that cell adhesion and phenotype can be regulated in vitro by peptide presentation, the importance of these manipulations to in vivo tissue formation or regeneration is only recently becoming clear. Appropriate adhesion peptide presentation has been shown to regulate bone and cartilage formation by transplanted cells, 48,54 and matching of the degradation rate of the synthetic ECM to the rate of tissue formation in these systems greatly increases the extent and rate of tissue formation. 55 Co-transplantation of appropriate cell populations in these materials has also been demonstrated to lead to the formation of multicomponent tissues, and in one example led to the formation of tissues structurally and functionally resembling growth plates.…”

Polymers to direct cell fate by controlling the microenvironment

“…Multiple factors can be delivered sequentially, simultaneously, or both, and these techniques can be combined with DNA or RNAi delivery to enable long-standing protein expression [35] or abrogation of expression [36]. The physiologic relevance of control over factors availability in time and space has been demonstrated by differentiation of stem cells [37], regulation over the extent of vascular network maturation with time [31], enhanced delivery and integration of transplanted cells [38], and the simultaneous formation of vascular networks at distinct stages of maturation in distinct spatial compartments [28].…”

“…As the expression of these factors becomes known, controlled delivery may allow for in situ reprogramming to generate stem cell and differentiated cell populations. Detailed knowledge of cues regulating cell fate is already being exploited to design materials that direct stem cell fate in vivo [38].…”