Transdifferentiation: a new promise for neurodegenerative diseases

Abstract

Neurodegenerative diseases are characterized by a gradual loss of cognitive and physical functions. Medications for these disorders are limited and treat the symptoms only. There are no disease-modifying therapies available, which have been shown to slow or stop the continuing loss of neurons. Transdifferentiation, whereby somatic cells are reprogrammed into another lineage without going through an intermediate proliferative pluripotent stem cell stage, provides an alternative strategy for regenerative medicine and disease modeling. In particular, the transdifferentiation of somatic cells into specific subset of patient-specific neuronal cells offers alternative autologous cell therapeutic strategies for neurodegenerative disorders and presents a rich source of using diverse somatic cell types for relevant applications in translational, personalized medicine, as well as human mechanistic study, new drug-target identification, and novel drug screening systems. Here, we provide a comprehensive overview of the recent development of transdifferentiation research, with particular attention to chemical-induced transdifferentiation and perspectives for modeling and treatment of neurodegenerative diseases.

Fig. 1. Comparison between indirect and direct conversion of somatic cells into neurons.

Somatic cells can be converted into neurons either indirectly or directly. In the indirect conversion technology, fibroblasts can be first converted into iPSCs, by over-expressing Yamanaka’s TFs or into iNPCs, by temporarily over-expressing Yamanaka’s TFs in the presence of specific exogenous differentiation factors. In turn, iPSCs and iNPCS, when cultured in specific lineage differentiation medium, can generate neurons. However, neurons obtained from iPSCs are reprogrammed to the embryonic stage, thus loosing specific age-related and epigenetic features. In the direct conversion technology, age equivalent neurons can be obtained from astrocytes and fibroblasts either by pro-neuronal transcription factors (TFs) plus differentiation and maturation factors (induced Neurons, iNs), or by chemicals/small molecules (chemical-induced neurons, ciNs). iNs and ciNs are mature and functional neurons rapidly obtainable but with limitative regenerative capacities. Despite the multiple neuronal phenotypes, iNs present health concerns

Fig. 2. Chemical reprogramming of fibroblasts to neurons.

A totally chemical approach can be used to direct reprogram fibroblasts to functional human neurons that retain the patient-specific signature such as age, epigenetic information, and pathological features. The fluorescence image in the scheme shows human ciNs, obtained from fibroblasts, labeled with antibodies against MAP2 (green), Beta III Tubulin (red), and nuclei counterstained with Hoechst (blue)

Fig. 3

Transdifferentiation in vivo. In situ astrocytes can be reprogrammed in the diseased brain by using different approaches, thus representing a promising tool for regenerative medicine