Tian Hu

Dedifferentiation and Regenerative Medicine: The Past and the Future

The turnabout of cellular differentiation, which is named as dedifferentiation or cytodedifferentiation, has enchanted biologists for many decades. The term cellular dedifferentiation was initially formulated by researchers who would like to describe the general dissociation or histolysis of tissues that occurred in the proximity to amputation plane following the loss of a limb or tail. Although scientists could reprogram cells in culture, in vivo cellular reprogramming or cellular dedifferentiation has recently emerged in both vertebrate and invertebrate, allowing for analyzing this fascinating process under more specific and physiologically relevant circumstances. Myofibers, Schwann cells, periosteal cells, and connective tissue cells dissociated and formed mononucleated cells that migrated to the distal end of the stump where they formed a regeneration blastema under the wound epithelial cap. Researches have demonstrated that dedifferentiation emerged not only during the large-scale process of cellular regeneration but also at low levels to restore stem cells that are lost or damaged within normal turnover. Although dedifferentiation is poorly understood, it has the potential to generate numerous cell types for disease therapy. This review has summarized the chronological profile of achievement in the field of cellular dedifferentiation in both zoology and phytology. As the last chapter of this book, the vista of future research on this field was included with accent on interpreting dedifferentiation by cutting-edge methods and novel perspectives.

Dedifferentiation and Musculoskeletal Repair and Regeneration

The majority of musculoskeletal diseases do not cause high mortality rate in patients as cancer and cardiovascular disease do. Rather, degeneration and injury of articulate bone and skeletal muscle would pose a grave threat to the quality of life. Adult articular cartilage possesses an extremely low self-regeneration ability owing to its avascular nature. Articular cartilage surface’s regeneration is decisive to inhibit the progression to osteoarthritis. Besides, osteogenesis deprives from mesenchymal stem cells (MSCs) differentiating into mature osteoblasts and bone formation’s each period is inseparable from assorted biological molecules’ delicate regulation. Of note, understanding the sophisticated circuit between osteogenic homeostasis and underlying mechanism is of tremendous value for artificial skeletal regeneration for severe bone defects. Adult skeletal muscle regenerates upon practice, muscle trauma, or degeneration. Satellite cells are muscle-resident stem cells and play substantive functions in regeneration and muscle development. Muscle regeneration recapitulates muscle development’s process in a large number of facets. In certain muscle diseases, heterotopic ossification or ectopic calcification, as well as fibrosis and adipogenesis, takes place in skeletal muscle. The author focuses on the issue of chondrocyte dedifferentiation, autologous chondrocyte transplantation, bone regeneration, and osteoblast and myotube dedifferentiation and compares and illustrates the difference of regenerative capacity between zebrafish, amphibians, and mammals. Specifically, molecular mechanisms of chondrocyte dedifferentiation and myotube dedifferentiation in distinct conditions are described in detail.

Dedifferentiation and Adipose Tissue

The attempt of adipocyte dedifferentiation is not for fat tissue repair or regeneration, since few would like too much fat tissue in their body. Attention has been long attracted by white adipose tissue because of its reversible and great capacity for expansion, which appears to be permanent throughout adult life. Adipose tissue enlargement is the result of adipocyte hypertrophy and the recruitment and differentiation of regenerative precursors that are situated in the stromal vascular fraction. The capillary network’s development, however, is also required to guarantee adipose tissue remodeling. Indeed, a decisive link exists between the capillary network and adipose cells. Endothelial cells and adipocytes own a common progenitor. Such adipose lineage cells take part in vascular-like structure and enhance the neovascularization reaction in ischemic tissue. Adipocytes are ideal cell type for mesoderm-derived tissue repair and regeneration. The dedifferentiated fat cells have the ability to redifferentiate into osteoblasts, chondrocytes, smooth muscle cells, and neurons. Besides, the dedifferentiated fat cells show the advantages of easy accessibility, which could be a wonderful substitute of mesenchymal stem cells. The author has summarized relevant knowledges of dedifferentiated fat cells’ gene expression, underlying signaling mechanism and multilineage differentiation potentials. The application of these potentials could shed light on osteogenesis, chondrogenesis, angiogenesis, and neurogenesis.

Dedifferentiation and Kidney System

Renal cell dedifferentiation, redifferentiation, and proliferation could resort to kidney repair and regeneration both theoretically and practically. The vertebrate kidney has an intrinsic capability to regenerate following acute impairment. Impaired tubular epithelial cells’ rapid alternate and reconstitution of ordinary tubular role are required by the injured kidney’s successful regeneration. Identifying the cells participating in the regeneration process as well as the molecular mechanisms implicated may unveil therapeutic objectives for kidney disease’s therapy. Renal regeneration is connected with the expression of genetic pathways requisite for kidney organogenesis, indicating that the regenerating tubular epithelium may be “reprogrammed” to a less-differentiated, progenitor state. Proximal tubular cell and podocyte dedifferentiation serve as two critical approaches of regenerative medicine in nephrology. For acute kidney injury, proximal tubular cell damage is the main pathophysiological reason. The mechanism and morphological changes of proximal tubular cell dedifferentiation, redifferentiation, migration, and proliferation are articulated in this review. Several sorts of stem cells, like bone marrow-derived cells, adipocyte-derived mesenchymal stem cells, embryonic stem cells, and induced pluripotent stem cells, are utilized for renal regeneration in a similar way. Endogenous or lineage reprogrammed renal progenitor cells symbolize a magnetic probability for differentiation into multiple renal cell types. Additionally, podocyte dysfunction could bring about other categories of nephron-related disease, such as diabetic nephropathy and HIV-associated nephropathy. Interestingly, podocyte dedifferentiation is observed in the usual pathological process of HIV-associated nephropathy, which could provide an excellent research model for exploring underlying mechanism of podocyte differentiation.

Dedifferentiation and Organ Regeneration

Regenerative medicine is an emerging research trend in current biology and medicine. The envious ability of regeneration in lower animals has attracted generations of scientists to explore and investigate the underlying mechanisms. The organogenesis, or organ regeneration, which is composed of parenchyma, functioning cell populations, and vasculature, is indispensable for terrestrial life. In recent years, extensive progress was done in defining organ development’s temporal progression, and exciting findings have been led to by this, including the derivation of assorted epithelium from pluripotent stem cells and the discovery of developmental pathways that are objectives for novel therapeutics. Fresh insights have been also provided by these discoveries into different organs’ regenerative capability. In this review, the author highlights several important and productive research areas in current regenerative medicine. Different animal models are studied with emphasis on specific organs in these animals, ranging from the regeneration of salamander limb, Xenopus tadpole tail, to zebrafish heart and fin. Molecular mechanism is the core content of relevant research, which could be modified and manipulated in the translation to human-based researches and clinical practice. In addition to the common research direction of growth factor, signaling pathway, transcription factors, and epigenetic modulation, this review has also included progenitor cells and potentials of dedifferentiation and transdifferentiation.

Peripheral Nerve Regeneration and Dedifferentiation

Peripheral nerve regeneration is one of the few processes that have been deeply investigated by scientists and researchers for a long time in the field of regenerative medicine. Anesthesia, paralysis, and lack of autonomic control of the affected body areas are results of peripheral nerve lesions. After trauma, axons distal to the injury are disconnected from the degenerate and neuronal body, bringing about the peripheral organs’ denervation. A microenvironment is created by Wallerian degeneration distal to the lesion site supporting axonal regrowth, whereas the neuron body switches in phenotype to boost axonal regeneration. Axonal regeneration’s importance is to substitute the degenerated distal nerve section and attain target organs’ reinnervation and restitution of their roles. In comparison with the central nervous system, the peripheral nerve could be easily obtained and dissected. In addition, several animal models of the peripheral nerve system have provided wonderful experimental materials for generations of scientists. Schwann cell dedifferentiation is the initial phase of peripheral nerve regeneration. And the model of Wallerian degeneration demonstrates one excellent biological process, which the repair and regeneration are orchestrated by certain sorts of cells. This review has summed up current studies on peripheral nerve regeneration, Schwann cell dedifferentiation, and the underlying molecular mechanisms. Among the molecular mechanisms, critical signaling pathways responsible for Schwann cell dedifferentiation and epigenetics were illustrated in detail.

Blood Vessel Repair, Atherosclerosis, and Dedifferentiation

Muscle cells could be briefly divided into skeletal muscular cells and smooth muscle cells in definition. While skeletal muscles were described in the previous chapter, so this article pays attention to the dedifferentiation issue of smooth muscle cell. Vascular smooth muscle cells (SMCs) retain remarkable plasticity to alternate from a differentiated to a dedifferentiated phenotype at local environmental cues or distinct developmental phases. The cellular switching process of SMCs from a quiescent contractile differentiated phenotype connected with smooth muscle-specific marker genes’ high expression, like smooth muscle 22α, calponin and α-smooth muscle actin, to a synthetic dedifferentiated phenotype associated with the marker genes’ diminished levels plays a decisive part in a large number of proliferative vascular diseases. This phenotypic alteration is regarded as essential for vascular repair. For assorted cardiovascular diseases, the inhibition of abnormal switching and the control of SMC proliferation, nonetheless, are crucial therapeutic strategies. Smooth muscle cells have demonstrated as one ideal research model for phenotypic modulation, dedifferentiation, redifferentiation, cellular plasticity, and switching. Owing to the high incidence and mortality of atherosclerosis, various researchers have devoted themselves into smooth muscle cell-related researches. This review has summed up the current knowledges of blood vessel repair, smooth muscle cell differentiation, and dedifferentiation. Transcription factors, epigenetic modulations, and miRNAs are illustrated as underlying molecular mechanisms.

Dedifferentiation and the Heart

Mending a broken heart is not only a thing people do when their feelings and sensibilities get hurt, but it is also the dream for generations of cardiologists. Heart disease, or cardiovascular diseases, constitutes one leading cause for current morbidity and mortality. Scientists and physicians could only modulate patients’ heart function or use supportive methods on heart disease. The ability of heart regeneration in lower vertebrate animals has got quite admiring looks from us human beings. Accordingly, the mechanisms of heart regeneration in animals and the barriers of that in humans have got intensive investigations. Nowadays, the centrosome has been found to be associated with cardiomyocyte proliferation. The dissolution of a centrosome would halt cardiomyocyte proliferation and bog down the cell cycle in G0/G1 phase. And relevant underlying mechanism has been intensively investigated, including the barrier of human cardiomyocyte proliferation, manipulation of reentering cell cycle, epigenetic regulation of cardiomyocyte regeneration, and other stem cells or progenitor cells in the heart. The author has compiled current researches and literatures on the heart regeneration model, cardiomyocyte dedifferentiation, and the cell cycle regulation of cardiomyocytes. New techniques and perspectives are also included in this review, such as small molecular regulator, miRNA, and epigenetic modulations.

Authors’ Related Publications

In many regenerative models, differentiated cells and adults structures could dedifferentiate into a relatively undifferentiated state or precursor cells. Dedifferentiation, as the initial step of this process, has attracted generations of scientists. The phenomenon of dedifferentiation was usually observed in lower vertebrates, for example the blastema in amphibian limb regeneration. Nowadays, cell dedifferentiation could also be induced or manipulated in mammals. Pro. Xiaobing Fu, the chief editor and author of this book, and his colleagues reported that the differentiated epidermal cells dedifferentiated into stem cells-like cells in patients’ wound treated with recombinant human epidermal growth factor in the Journal of Lancet in 2001. Since then, his group have explored and investigated numerous areas on the process of dedifferentiation and achieved plenty of research outcomes. The topics of these researches from his group covered epidermal cell dedifferentiation, iPSCs, skin regeneration, skin stem cells, reprogramming, and cell plasticity. Hereinafter the abstracts of twelve articles and reviews from this research group are presented in this chapter.

Cellular Dedifferentiation and Regenerative Medicine

Central nervous system serves as the leading organ controlling, manipulating, and involving into almost every aspects of human body’s functions. Researches and neuroscientists have been trying to find out varieties of approaches to repair and restore the damaged or degenerated central nervous system. It is generally believed that there are hundreds of billions of neurons in our brain, and the quantity would not change after birth. The olfactory bulb and hippocampus are the only two regions that could undergo self-renewal during our lifetime. Neural stem cells could differentiate into neuronal restricted progenitors and glial restricted progenitors. Glial restricted progenitors could produce type I astrocytes, type II astrocytes, and oligodendrocytes. But the regenerative capacity of these stem cells is far insufficient. Dedifferentiation of certain types of cells that resided in the central nervous system has provided the opportunity for neural regeneration, since other approaches, such as transplantation or drugs, could hardly take effects. Specifically, astrocyte dedifferentiation was observed successfully both in vivo and vitro. Injury triggers the dedifferentiation in vivo, while astrocytes could be reprogrammed to dedifferentiated types in vitro. This review summarized the current understandings and researches on central nervous regeneration, astrocyte differentiation, and direct reprogramming of astrocytes. In order to achieve the goal of CNS regeneration, clarifying the molecular mechanisms of regulating dedifferentiation and redifferentiation in situ would lay the solid foundation for further researches.