This article summarizes the results of three basic research approaches directed toward achieving the restoration of injured or diseased human tissues. The three approaches are (1) to understand the differences in the molecular characteristics of cells and their environments in tissues which exhibit regenerative capacity at one stage of the life cycle but not at another; (2) to understand the molecular mechanisms whereby tissues regenerate by means of reserve progenitor cells or progenitor cells formed by dedifferentiation; and (3) to design artificial tissues for implantation into the body. These strategies should allow us to locate the key switchpoints which determine regeneration versus repair and how to reconfigure those switchpoints into a regenerative circuit where necessary or to build tissues in vitro that can serve as in vivo substitutes. For these strategies to be successful, we must understand the role of the immune system in repair and regeneration and the developmental roles of regulatory molecules, such as growth factors, trophic factors, extracellular matrix components, and the protein products of patterning genes, as well as the intracellular signaling systems activated by these molecules. The examples used to illustrate these themes are repair versus regeneration in wounded mammalian skin, the regeneration of injured mammalian bone and muscle by reserve progenitor cells, and the regeneration of the urodele limb, neural retina, and lens by progenitor cells produced by dedifferentiation. In addition, several approaches used in the construction of bioartificial tissues are discussed.

Journal Article↗

PubMedDate not supplied

Regenerative biology and engineering: strategies for tissue restoration.

Over the past 50 years, we have made remarkable advances in the use of bionic devices and solid organ transplants as replacement parts for failing tissues and organs. These approaches to tissue restoration, however, have a number of drawbacks. Thus, a new approach, regenerative biology and engineering, has been developed, consisting of the strategies of cell transplantation, bioartificial tissue constructs, and stimulation of regeneration in vivo. Cell transplants have been successfully used to restore articular cartilage and to treat Parkinson's disease in humans. In rats, transplanted fetal and embryonic stem cell line-derived cardiomyocytes have been shown to differentiate and integrate well with the ventricular myocardium, suggesting the feasibility of using such transplants to restore damaged cardiac muscle. Diabetic symptoms in humans have been alleviated by implanting a bioartificial pancreas consisting of islet cells microencapsulated in alginate. Hydroxyapatite matrixes can stimulate the regeneration of bone across large gaps. Collagenous artificial matrixes can stimulate the regeneration of dermis, and peripheral nerve grafts embedded in a fibrin clot containing fibroblast growth factor-1 stimulate some regeneration of spinal cord axons in adult rats. Future research in regenerative biology will focus on several issues: (1) providing adequate sources of cells for transplantation and bioartificial tissue construction and determining ways to prevent these cells from coming under attack by the immune system, (2) developing new and better materials to build better bionic devices and bioartificial constructs and to stimulate regeneration in vivo, (3) determining how many tissues of the body might contain reserve cells for regeneration in vivo, (4) analyzing the molecular differences between cells and environments of regenerating versus nonregenerating tissues, and (5) understanding the factors and mechanisms involved in the proliferation and patterning of regenerating tissues.

Adult↗

PubMedDate not supplied

Stem cells in regenerative biology and medicine.

Embryonic stem cells of the mammalian blastocyst give rise to all the tissue lineages that begin to emerge at gastrulation. They are pluripotent cells and can be propagated in vitro without loss of pluripotency. Many adult tissues harbor cells that do not complete their differentiation program. These cells serve as self-renewing stem cells whose normal fate is to regenerate site-specific tissue, in response to either physiological cell turnover or damage inflicted by injury or disease. Neural, muscle, and bone marrow stem cells possess developmental potency far greater than their normal lineage-restricted fate. The understanding of the biology of stem cells is leading us into an era of regenerative medicine. The growth potential and pluripotency of embryonic stem cells and the developmental plasticity of adult stem cells, particularly those of bone marrow, make them potentially useful for replacing tissues, via transplantation or construction of bioartificial tissues, that either do not regenerate naturally or are damaged beyond their natural capability for regeneration. In addition to these two ways of replacing tissue, a third strategy of regenerative medicine is to stimulate regeneration in vivo from resident stem cells. Before these approaches become clinical reality, however, a number of basic research issues must be resolved, including the revision of our concept of a regeneration-competent cell.

Bone Marrow Cells↗

PubMedDate not supplied

[Regulation of the spatial organization of the regenerating extremity in amphibians].

Tests of the morphogenetic potency of the urodele limb regeneration blastema by a variety of transplantation experiments indicate that blastema is a self-organizing system. The cells of blastema inherit a memory of their position on the three cardinal axes of the limb. This memory is called positional memory, and it is fundamental to recognizing loss of structure, triggering cellular interactions to replace missing structures, and specifying the level from which new structures can begin. Retinoic acid (RA) modifies the positional memory in all three cardinal axes of the limb. The vitamin proximalizes positional memory in the proximodistal axis, posteriorizes it in the anteroposterior axis, and ventralizes it in the dorsoventral axis. In vivo and in vitro assays of interactions between cell derived from different proximodistal limb levels, before and after treatment with RA, suggest that the cellular basis of positional memory resides in recognition/affinity property of the cell surface. RA probably modifies positional memory by modulating transcription, via a nuclear retinoid receptor. It is suggested that the genes involved in specifying positional memory, and whose transcription is therefore affected in regenerating limbs, are homeo box genes and genes that encode for molecules involved in determining the composition and architecture of the cell surface and extracellular matrix.

Amphibians↗