Regenerative Medicine with Stem Cells

Introduction

Large numbers of people are suffering from noncommunicable chronic diseases all over the world. The ageing population is afflicted by a variety of degenerative diseases. Progressive cell destruction leading to irreversible loss of tissue function has necessitated innovative modalities of therapy. It forms the basis of regenerative medicine. It aims at providing care from palliation-to-cure.¹ Regenerative medicine is a process of creating, living functional tissues to repair or replace tissues or organ functions lost due to damage or congenital defects.

The success from bone marrow transplants to the recent breakthroughs in neo-organogenesis, have shown great promise in repair of pathological states and restoration of organ function in a variety of congenital abnormalities to age-related disorders.

Self-repair process

The self-repair processes exist in the body and they are active throughout our life. But they have great limitations as those mechanisms of innate healing are only capable of maintaining tissue homeostasis in health. In large scale tissue destruction selfrepair is insufficient to ensure adequate repair and restoration of function. This led to the emergence of transplant medicine replacing the organs that are failing in their function. Renal transplantation, cornea grafting, liver transplantation, heart transplantation, lung transplantation are some of the examples of organ transplantation. However this has marked limitation due to a shortage of organs available for donation compared to the number of patients who require life saving organ transplants.

New technologies

In order to overcome this, new technologies have attempted to repair the structure and function of failing organs through tissue generation. The developments in stem cell research have led to the emergence of cellular therapy. Stem cell-based regenerative strategies involve engraftment of progenitor cells that, through growth and lineage specification, supplement and recruit resident progenitor pools, and enable reconstruction of damaged tissues.¹

Stem cells

Stem cells are of four types such as embryonic stem cells, perinatal stem cells, adult stem cells and bioengineered stem cells.

1. Embryonic stem cells:

   Embryonic stem (ES) cells are pluripotent and are derived from the inner cell mass of the embryo at the blastocytst stage. They are capable of giving rise to all tissues of three embryological germ layers consisting of ectoderm, endoderm and mesoderm, when allowed to differentiate within the appropriate microenvironment. Ethicality of embryo destruction has restricted its use in clinical setting.

2. Perinatal stem cells:

   The sources of perinatal stem cells are umbilical cord blood and amniotic fluid-derived stem cells. The progenitor cells from umbilical cord blood have the capability of producing haematopoietic and non-haematopoieic lineages.² They have also the capability to behave like embryonic stem cells. Amniotic fluid-derived stem cells can produce lineages involving the production of bone, myocardium, endothelium, liver and nerve tissues.³

3. Adult stem cells:  

   The bone marrow, blood and adipose tissue are the tissues that form the main source for the adult stem cells. Unlike the embryonic stem cells, the adult stem cells possess a more restricted multipotent differentiation capacity.⁴ They give rise to specialized cell types restricted to an embryological germ layers. Stem cell regenerative strategies have been essentially carried out using the adult stem cells. They have been used successfully in the treatment of multiple myeloma, lymphoma, leukaemia, and autoimmune disorders. Clinical trials are attempting to widen their use in treatment of disorders affecting neurologic, cardiovascular, endocrine and musculoskeletal SYSTEMS.⁵

   Though the usefulness and safety of adult stem cell therapy has been established, Terzic and colleagues have noted the following limitations for their use.¹ They are variable functional parameters for cell isolation and delivery, transplant of heterogeneous cell population exhibiting different degrees of reparative capacity, inter-patient variability, difficulties in the selection of patients most likely to respond to stem cell therapy, recognition of the ideal timing of intervention, and of the most favourable route of administration, low rates of cell retention, advanced age of the patient, existence of co-morbid conditions, and underlying diseases.

4. Bioengineered stem cells:

   Successful attempts have been made to achieve pleuripotency in non-stem cells. Two different techniques have been used to produce them. They are somatic cell nuclear transfer (SCNT) and pluripotency induced by factor-mediated nuclear reprogramming.⁶ The somatic cells are well differentiated in adults and do not spontaneously get altered. It is possible to redirect the somatic cells by perturbations in the stiochiometry of transcriptional regulators present in each cell of the human body.⁷ Somatic cell nuclear transfer involves transfer of a somatic cell nucleus into an enucleated oocyte. It leads to the production of a cloned zygote from which embryonic stem cells can ultimately be obtained. This technique known as cloning was used to create the sheep Dolly.⁸

Nuclear reprogramming

Nuclear reprogramming of ordinary fibroblasts can be achieved through the retroviral insertion of four transcription factors into the genome and achieve pluripotency of somatic cells. They will be capable of expression of gene profiles typical of an embryonic stem cell, returning the cell to an embryonic-like state. Such bioengineered cells are called induced pluripotent stem cells (iPS) and are capable of differentiation into tissues of all lineages.⁷

Nuclear reprogramming technology offers a revolutionary technology for embryo-independent derivation of pluripotent stem cells from somatic adult cells. This technology avoids the ethical concerns regarding embryo destruction that limit the use of human embryonic stem cells (9). It provides an unlimited renewable pool of new tissues obtained from the patient’s own cells. It must be noted that all iPS cells do not exhibit longitudinal functional equivalence to human embryonic stem cells.

iPS technology needs further improvements in the protocols to improve its efficiency and safety for clinical applications. There is also a danger of iPS cells getting transformed into a dysplastic growth from an insertional mutagenesis due to the retroviral transduction of transcription factors into the genome. The iPS technology has the advantage of avoiding the need for immunosuppression. It provides an unlimited resource capacity as it requires only a tissue biopsy for derivation. The tissue donation process for iPS production appears safe and less invasive. The process avoids the ethical concerns regarding embryo destruction.⁹ Thus iPS techology has the capability of offering a potentially viable alternative to human embryonic cells without causing any destruction of human embryos. The day is not far off to replace embryonic stem cells by iPS cells in most situations. Still a long way has to be treaded to use the bioengineered cells.