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Transactivator protein: An alternative for delivery of recombinant proteins for safer reprogramming of induced Pluripotent Stem Cell

Nordin F, Ahmad RNR, Farzaneh F

Virus Res, 2017 05 02;235:106-114.
PMID: 28408207 DOI: 10.1016/j.virusres.2017.04.007

Induced pluripotent stem cells (iPSC) are somatic cells reprogrammed to pluripotency by forced expression of pluripotency factors. These cells are shown to have the same pluripotent potential as embryonic stem cells (ESC) and considered as an alternative to the much controversial usage of ESC which involved human embryos. However, the traditional method in reprogramming cells into iPSC using genome-integrating retro- or lenti- viruses remains an obstacle for its application in clinical setting. Although numerous studies have been conducted for a safer DNA-based reprogramming, reprogramming of iPSC by genetic modifications may raise the possibility of malignant transformation and has been a major limitation for its usage in clinical applications. Therefore, there is a need for an alternative method to reprogram the cells without the use of gene editing and a much safer way to deliver transcription factors to induce pluripotency on target cells. Using protein transduction approach, a number of studies have demonstrated the generation of human iPSCs from human fibroblasts and mouse embryonic fibroblasts by direct delivery of reprogramming proteins. In this review, the definition and mechanism of HIV-TAT protein (a type of protein transduction domain) in delivering recombinant proteins, including the potential of protein-based delivery to induce iPSC were further discussed.

Matched MeSH terms: Induced Pluripotent Stem Cells/physiology*
Current techniques in reprogramming cell potency

Romli F, Alitheen NB, Hamid M, Ismail R, Abd Rahman NM

J Cell Biochem, 2013 Jun;114(6):1230-7.
PMID: 23239017 DOI: 10.1002/jcb.24477

The first successful attempt to reprogram somatic cell into embryonic-like stem cell was achieved on 2006. Since then, it had sparked a race against time to bring this wonderful invention from bench to bedside but it is not easily achieved due to severe problems in term of epigenetic and genomic. With each problem arise, new technique and protocol will be constructed to try to overcome it. This review addresses the various techniques made available to create iPSC with problems hogging down the technique.

Matched MeSH terms: Induced Pluripotent Stem Cells/physiology*
Reprogramming cancer cells: overview & current progress

Lim KL, Teoh HK, Choong PF, Teh HX, Cheong SK, Kamarul T

Expert Opin Biol Ther, 2016 07;16(7):941-51.
PMID: 27070264 DOI: 10.1517/14712598.2016.1174211

INTRODUCTION: Cancer is a disease with genetic and epigenetic origins, and the possible effects of reprogramming cancer cells using the defined sets of transcription factors remain largely uninvestigated. In the handful of publications available so far, findings have shown that reprogramming cancer cells changed the characteristics of the cells to differ from the parental cancer cells. These findings indicated the possibility of utilizing reprogramming technology to create a disease model in the laboratory to be used in studying the molecular pathogenesis or for drug screening of a particular cancer model.
AREAS COVERED: Despite numerous methods employed in generating induced pluripotent stem cells (iPSCs) from cancer cells only a few studies have successfully reprogrammed malignant human cells. In this review we will provide an overview on i) methods to reprogram cancer cells, ii) characterization of the reprogrammed cancer cells, and iii) the differential effects of reprogramming on malignancy, epigenetics and response of the cancer cells to chemotherapeutic agents.
EXPERT OPINION: Continued technical progress in cancer cell reprogramming technology will be instrumental for more refined in vitro disease models and ultimately for the development of directed and personalized therapy for cancer patients in the future.

Matched MeSH terms: Induced Pluripotent Stem Cells/physiology
In vitro generation of functional insulin-producing cells from lipoaspirated human adipose tissue-derived stem cells

Mohamad Buang ML, Seng HK, Chung LH, Saim AB, Idrus RB

Arch Med Res, 2012 Jan;43(1):83-8.
PMID: 22374243 DOI: 10.1016/j.arcmed.2012.01.012

BACKGROUND AND AIMS: Tissue engineering strategy has been considered as an alternative treatment for diabetes mellitus due to lack of permanent pharmaceutical treatment and islet donors for transplantation. Various cell lines have been used to generate functional insulin-producing cells (IPCs) including progenitor pancreatic cell lines, embryonic stem cells (ESCs), umbilical cord blood stem cells (UCB-SCs), adult bone marrow stem cells (BMSCs), and adipose tissue-derived stem cells (ADSCs).
METHODS: Human ADSCs from lipoaspirated abdominal fat tissue was differentiated into IPCs following a two-step induction protocol based on a combination of alternating high and low glucose, nicotinamide, activin A and glucagon-like peptide 1 (GLP-1) for a duration of 3 weeks. During differentiation, histomorphological changes of the stem cells towards pancreatic β-islet characteristics were observed via light microscope and transmission electron microscope (TEM). Dithizone (DTZ) staining, which is selective towards IPCs, was used to stain the new islet-like cells. Production of insulin hormone by the cells was analyzed via enzyme-linked immunosorbent assay (ELISA), whereas its hormonal regulation was tested via a glucose challenge test.
RESULTS: Histomorphological changes of the differentiated cells were noted to resemble pancreatic β-cells, whereas DTZ staining positively stained the cells. The differentiated cells significantly produced human insulin as compared to the undifferentiated ADSCs, and its production was increased with an increase of glucose concentration in the culture medium.
CONCLUSIONS: These initial data indicate that human lipoaspirated ADSCs have the potential to differentiate into functional IPCs, and could be used as a therapy to treat diabetes mellitus in the future.

Matched MeSH terms: Induced Pluripotent Stem Cells/physiology*
Fulltext Development and Differentiation of Midbrain Dopaminergic Neuron: From Bench to Bedside

Wang M, Ling KH, Tan JJ, Lu CB

Cells, 2020 06 18;9(6).
PMID: 32570916 DOI: 10.3390/cells9061489

Parkinson's Disease (PD) is a neurodegenerative disorder affecting the motor system. It is primarily due to substantial loss of midbrain dopamine (mDA) neurons in the substantia nigra pars compacta and to decreased innervation to the striatum. Although existing drug therapy available can relieve the symptoms in early-stage PD patients, it cannot reverse the pathogenic progression of PD. Thus, regenerating functional mDA neurons in PD patients may be a cure to the disease. The proof-of-principle clinical trials showed that human fetal graft-derived mDA neurons could restore the release of dopamine neurotransmitters, could reinnervate the striatum, and could alleviate clinical symptoms in PD patients. The invention of human-induced pluripotent stem cells (hiPSCs), autologous source of neural progenitors with less ethical consideration, and risk of graft rejection can now be generated in vitro. This advancement also prompts extensive research to decipher important developmental signaling in differentiation, which is key to successful in vitro production of functional mDA neurons and the enabler of mass manufacturing of the cells required for clinical applications. In this review, we summarize the biology and signaling involved in the development of mDA neurons and the current progress and methodology in driving efficient mDA neuron differentiation from pluripotent stem cells.

Matched MeSH terms: Induced Pluripotent Stem Cells/physiology