Stem cells are precursor undifferentiated cells that are characterised by self renewal and differentiation. The most common definition is based on the properties of hematopoietic stem cells such as multipotency, asymmetric divisions, quiescence, life- long self renewal, niche dependence and long term repopulation ability upon in vivo transplantation. All stem cells may not follow these properties like embryonic stem cells not self renewing in vivo beyond the blastocyst stage muscle cells are not multipoint; and mesenchymal stem cells do not transplant robustly. Based on context and organism, stem cell properties of monopotency, transient proliferation, lack of niche and inability to transplant in vivo are acceptable. Some stem cells like mesenchymal stem cells have the potential of generating cells not only of their lineage but also other lineages. This phenomenon is known as plasticity or transdifferentiation. Homeostatis is the central mechanism in mammalian cells through which stem cells maintain and preserve organ and tissue integrity by self renewal and multilineage differentiation. Stem cell populations are heterogeneous. Though stem cells express specific protein markers but accumulating evidence suggests that these markers are transient and dynamic. Stem cells express a vast range of genes at the mRNA levels. Stem cells undergo asymmetric mitotic division and produce two identical daughter cells. Of the two cells, at least one cell retains the stem cell properties, while other differentiates. This process is governed by stem cell niche (environment) and the detachment from this niche would result in differentiation. Stem cells may also follow stochastic differentiation, wherein stem cells make a combination of asymmetric divisions and symmetric ones leading to the formation of either two stem cells (symmetric renewal) or two differentiated cells (symmetric differentiation). Stem cells in olfactory epithelium and muscle follow this kind of cell division.
There is no consensus on the uniformity in the classification of stem cells in the literature. Stem cells were classified as embryonic or adult/non-embryonic/
somatic (postnatal to adult)/extra- embryonic stem cells (adult, cancer and induced pluripotent) or hematopoietic and non-hematopoietic (mesenchymal stem cells), based on their origin. In terms of developmental potential, stem cells were categorized as totipotent, multipotent and unipotent. Totipotent stem cells are
able to differentiate into all types of embryo tissues in the trophoblast. These cells are found after the first cell divisions in zygote (ex.zygote). Stem cell are pluripotent because of their ability to differentiate into cells of the three germinal layers (ectoderm, mesoderm and endoderm) except trophectoderm lineage.
Embryonic stem cells belong to this category. Multipotent stem cells like hemopoietic can produce a limited range of differentiated cell lineages. Only one specific cell type is generated by unipotent stem cells such as muscle progenitors.
Types of stem cells
Embryonic stem cells
- 1) These cells are primitive cells and can self renew and differentiate into all cells from all three germ layers such as ectoderm, endoderm and mesoderm.
- 2) Derived from inner cell mass of blastocyst stage at approximately five days of development using a immunosurgical technique.
- 3) Sources are embryos created via in vitro fertilisation/somatic cell nuclear transfer and fetuses obtained through elective abortion.
- 4) These cells do not conform to several cell requirements such as niche dependence, capacity to undergo asymmetrical cell division.
- 5) Mouse not human embryonic stem cells require leukemia inhibitor factor for their propagation.
- 6) These cells are grown on feeder layers.
- 7) These cells can be maintained in undifferentiated state for at least 80 passages.
- 8) They can form embryoid bodies, the cell aggregations containing all three embryonic germ layers.
- 9) These cells have the potential of forming teratomas in vivo.
- 10) These cells are considered as the optimal stem cell source for regenerative medicine applications in view of their potential to form any tissue in the
body. - 11) Application of these cells are limited by ethical, political, biologic and regulatory hurdles.
Epiblast-stem cells (EpiSC)
1) Cells are derived from pre- gastrula embryo.
2) Express surface markers like mouse embryonic stem cells, Oct4, Nanog and Ssea-1, and form teratoma.
3) These cells do not require feeders or leukemia inhibitory factor (Lif) for culture but can be expanded in the presence of Activin/nodal signaling.
4) These cells are unable to contribute to somatic cells and the germ line following injection into blastocyst or following morula aggregation.
XEN Stem cells
- 1) These cells are isolated from extra embryonic endoderm.
- 2) Express markers like Sox7, Hnf4, Gata4 and Foxa2 but lack expression of Oct4 and Nanog.
- 3) In a chimera assay, these cells contributed to the parietal endoderm and to the parietal yolk sac at later stages during embryo development.
XEN P Stem cells
- 1) Express genes Oct4, Gata 6 and Ssea-1 and isolated from rat blastocysts.
- 2) These cells require leukemia inhibitory factor (Lif) for exvivo maintenance.
- 3) Upon morula aggregation or injection in the blastocyst, these cells contribute to primitive/visceral and parietal extra embryonic endodermal lineages but not the embryo proper.
- 4) They form tumors when injected postnatal.
Hematopoietic stem cells (HSCs)
- 1) These are best characterised stem cells.
- 2) The size of the total pool of HSCs remains roughly the same in the absence of injury, about half of all HSC divisions must, at the population level, be self-renewing.
- 3) In the steady state, HSCs redistribute via the bloodstream among distinct anatomical locations and therefore are likely to be found in all tissues of the body. 4) These cells are multipotent and can differentiate into all myeloid and lymphoid blood lineages.
- 5) Through fusion HSC contribute to other tissues.
- 6) Sources of these cells are bone marrow, peripheral blood and umbilical cord blood.
- 7) These stem cell transplantations are performed using HLA matched siblings, parents or donors.
- 8) These cells represent less than 0.05% of the total bone marrow.
- 9) Enriched using a complement of cell surface antigens.
Mesenchymal Stem cells
- 1) These are adherent cells with fibroblast like morphology and are capable of self replication through many passages.
- 2) These cells are pluripotent and are capable to differentiate into multiple types of tissue like bone, cartilage, muscle, neuron, cardiomyocyte and hepatocytes.
- 3) These cells have proangiogenic and immunomodulatory effects.
- 4) These cells have the potential utility for treating a variety of diseases and disorders like graft versus host disease, organ transplantation, cardiovascular disease, brain and spinal cord injury, lung, liver and kidney diseases and skeletal injuries.
- 5) They have conserved long telomere lengths and do not form teratomas in vivo.
- 6) These cells are isolated from a number of tissues like bone marrow, adipose tissue, umbilical cord blood, placenta, amniotic fluid, amniotic membrane,
- gingival, circulating blood, synovium, trabecular bone, dermis, dental pulp and lung and have the capacity of expansion in vitro on a clinical scale.
- 7) These cells participate in maintaining essential environment to support the hematopoietic stem cells in the bone marrow.
Pancreatic stem cells (PSC)
- 1) They provide an alternative renewable source of surrogate â cells.
- 2) They have the potential for lineage-restricted differentiation and are capable of developing into a pancreatic phenotype.
- 3) The adult pancreatic stem or progenitor cells are found in duct cells, exocrine tissue, nestin positive islet-derived progenitor cells, neurogenin-3-positive cells, pancreas-derived multipotent precursors and mature â cells.
- 4) In the present state of knowledge, the expansion potential of PSC is limited.
- 5) Pdx-1, nestin and Ngn-3 markers have been shown to be expressed by these cells.
Cancer stem cells (CSCs)
- 1) These are small population of cancer cells that have the ability of unlimited growth, self renewal, as well as differentiation into more specialised cancer
- cell types.
- 2) CSCs have been identified and isolated in various hematological as well as solid malignancies.
- 3) CSC may form new tumour tissue when transferred into immunodeficient animal models and have been shown to survive and regenerate tumours tissue even after large percentage of tissues has been destroyed by chemotherapy.
- 4) Standard pathways for self-renewal of normal stem cells, such as Wnt, Notch and Hedgehog signaling, are also present in CSCs and have an important
- role in their function.
- 5) These cells produce higher levels of proangiogenic factors than their differentiated counterparts, and exhibiti more potent proangiogenic capability.
Applications
- 1) Stem cells provide an opportunity to study the growth and differentiation of cells into tissues.
- 2) Stem cells can be used to produce large amounts of one cell type.
- 3) These cells can be to test new drugs for effectiveness and chemicals for toxicity.
- 4) The damaging side effects of medical treatments might be repaired with stem cell treatment.
- 5) Somatic cell nucleus transfer technique stem cells created by using patient cell would avoid any tissue rejection problems that could be encountered in
- other stem cell therapeutic approaches.
- 6) In view of their migratory properties these cells can be used to target organs ex.tumours.
- 7) These cells can be used as vehicles to carry therapeutic molecule which they excrete spontaneously.
- 8) Stem cell therapies, in future, may circumvent the traditional use of chemicals as therapeutic drugs.
- 9) Stem cell transplantations are used to treat or greatly ameliorate a variety of genetic diseases ranging from inherent defects of hematopoietic cell production (thalassaemia) or function to metabolic diseases (lysosomal storage diseases) mostly affecting solid organs.
- 10) In acute myeloid leukemia and high grade lymphoma, hematopoietic cell therapy is used as adjuvant therapy.
- 11) Stem cells therapies are promising in the management of variety of disease conditions like cardiovascular diseases, neurological diseases (parkinson’s disease, Amyotrophic lateral sclerosis, Huntington’s diseases or Alzheimer’s disease, Duchenne muscular dystrophy), diabetes, eye diseases and bone
- diseases.
- 12) Mesenchymal stem cells have been shown to be helpful in rapid engraftment of allogenic bone marrow transplantations. These cells were found inhibiting T cell growth, reducing graft versus host disease and effective in a large number of steroid resistant patients.
- 13) Early wound healing, delayed progression in human multiple system atrophy and beneficial effects in patients with hemorrhagic cystitis, penmomediastium and perforated colon due to the transplantion of mesenchymal stem cells.
- 14) In experimental studies entire organs were generated from stem cells and this raises the hope of using stemcells/progenitors for tissue engineering applications to generate organs for therapeutic purposes.
Challenges: Overcoming the immunological barriers, understanding of tissue restrictive signals, betterment of methodologies for stem cell isolation, in vitro
propagation and transplantation either allo or xeno conditions by awakening resident stem cells, lineage tracing and long term real time follow-up of single
cells including the real time assessments of gene and protein expression may go a long way in better utilisation of stem cell therapies for improving the quality of life in people afflicted with various disease conditions.