La insurgencia y el gamonalato local: conflicto entre poderes

Stem cells are undifferentiated cells that can differentiate into specialized cells and divide (through mitosis) to produce more stem cells. Two important properties of all stem cells are the capability of unlimited self-renewal and the capacity to differentiate into various cell lineages (also known as pluripotency) of many tissue types (Cogle et al., 2003). Although this dual functionality has been much studied, the search for molecular signatures of ‘stemness’ and pluripotency is only now beginning to gather momentum. Stem cells are classified into four types: two physiological types present at different stages of life, embryonic stem cells (ES cells) and adult stem cells (ASCs); one engineered or ‘induced’ type, induced pluripotent stem (iPS) cells; and one pathological type present in cancers with some stem properties, cancer stem cells (CSCs) (Herreros-Villanueva et al., 2014). In the past decades, the majority of stem cell studies have focused on ES cells, and the knowledge generated from ES cell studies has guided investigations of the other three types of stem cells.

The second class of stem cells is ASCs, also known as somatic stem cells (SSCs), are thought to be postnatal derivatives of ES cells present throughout the body, including the skin, brain, bone marrow, intestine, and neural tissue. At least three of the core

ES cell transcription factors (OCT4, KLF4, and SOX2) have been reported to be regulated in ASCs (Alvarez et al., 2012). ASCs are primarily involved in maintaining and repairing/regenerating specific tissues; under certain circumstances, they may contribute to disease development. The ASCs for potential use in stem cell therapy are autologous; because they are usually harvested from the patient, there are almost no immunologic barriers. However, unlike ES cells, ASCs do not fully retain their proliferative and multi-lineage differentiation capabilities in aging humans (Boyette and Tuan, 2014), meaning they only maintain the capacity to differentiate into specific cell lineages from a given germ layer based on their origin. Furthermore, the same group also proved that ASCs are limited in quantity because of their lower capacity to divide during in vitro culture (Boyette and Tuan, 2014). Hematopoietic stem cells (HSCs) have been used in clinical settings for years to reconstitute the immune system in cancer and other illnesses, while other ASCs have been used as gene delivery vectors to enhance tissue regeneration, destroy cancer cells, and regenerate cartilage and bone (Boyette and Tuan, 2014).

Fifty years ago, Sir John Gurdon succeeded in a ground-breaking work to generate cloned frogs by transferring the nucleus of a tadpole's somatic cell into an oocyte, thus demonstrating that cells retain genetic information and can be rejuvenated by artificial treatment to again acquire pluripotency (Gurdon, 1962). Numerous other studies of nuclear reprogramming have since been conducted. In 2006, Shinya Yamanaka’s lab first generated the induced pluripotent stem cells (iPSCs) by transducing four key transcription factors, OCT4, SOX2, c-Myc, and KLF4, which are artificially engineered into adult cells (Takahashi and Yamanaka, 2006). iPSC generation is a milestone achievement in stem cell research, not only breaking the dogma that somatic

cell differentiation is an irreversible process, but also creating new avenues in disease modelling and regenerative medicine that avoid the controversial use or destruction of embryos required for ESC generation.

The final type of stem cell, CSC, is found within tumours. CSCs can self-renew, produce differentiated progeny, and drive tumorigenesis. The ability of cancer cells to form non-adherent spheroids in in vitro culture is frequently used as a surrogate marker for the stemness of CSCs (Alvarez et al., 2012).

Since the first report in 1998, human ESCs have been viewed as a key component of future treatments for diseases such as Parkinson's disease and spinal cord injury (Thomson, 1998). However, clinical applications and research using human ESCs face several barriers, including ethical concerns about the use of human embryos and scientific concerns about immune rejection after transplantation, which could be overcome by iPSC technology. Since Yamanaka’s group discovered iPSCs in 2006, accumulating evidence has demonstrated that iPSCs have properties similar to those of ES cells (unlimited self-renewal and the ability to differentiate into different cell types derived from the three germ layers: endoderm, mesoderm, and ectoderm), indicating that iPS cell technologies can be applied in medical science, in particular for regenerative medicine and human disease modelling (Takahashi and Yamanaka, 2006, Okano and Yamanaka, 2014).

Pluripotent stem cells have been used as a critical tool in regenerative medicine and tissue engineering for clinical cell therapies to treat devastating and incurable diseases, including type 1 diabetes, blindness, damaged articular cartilage, neurological diseases, Parkinson’s disease (PD), corneal diseases, and terminal cardiovascular

diseases (Boyette and Tuan, 2014, Hayashi et al., 2012, Kikuchi et al., 2011). Furthermore, the use of iPSCs in regenerative medicine to treat other diseases, including CVD, is under investigation worldwide (Chi et al., 2015, Wong et al., 2013, Egashira et al., 2011).

One important concern for iPS cell generation is the cellular source. Ideally, human iPSCs should be obtained using minimally invasive procedures associated with the lowest possible risk. In 2007, human iPSCs were first established from dermal fibroblasts by Yamanaka’s group (Takahashi et al., 2007). Thereafter, cord blood (CB) stem cells were reprogrammed to iPSCs by retroviral transduction with only two factors (OCT4 and SOX2) in 2 weeks and without the need for additional chemical compounds (Giorgetti et al., 2010). Moreover, another report has suggested that iPSCs can be generated easily from CD34+ cord blood cells by repressing p53 expression through the addition of a lentiviral p53 short-hairpin RNA expression vector (Takenaka et al., 2010).