Stem cell therapy is an important focus of biomedical research due to its healing ability especially for cancer treatment (chemotherapy or radiotherapy) and life threatening disease. The therapeutic motif is to replace the damaged or injured tissues with the healthy cells. Stem cell research helps to understand the core mechanisms of human development. In India as well as worldwide this treatment procedure has taken a good shape. Stem cell therapy can be useful in many complicated or untreatable diseases, like:
- Neurological issues: Alzheimer’s disease, Parkinson’s disease, spinal cord injury
- Heart muscle cells damage repair
Stem cells are like building blocks (raw data) within the body with self-renewal capacity, unspecialized nature and differentiation ability for long time.(ref) Stem cells mostly remain undifferentiated and become active (by division/differentiation) to produce daughter cells as require. The daughter cells could be the replica of the mother cell or different in function (e.g.: muscle cells, blood cells, brain cells). Stem cell idea was first introduced in 1963 by Till and McCulloch for their research work on blood system regeneration(ref).
Self-renewing capacity of stem cells help them to replicate/proliferate for many times.
Classes of Stem Cells
Three class of stem cells are found in human body system, namely Totipotent, Pluripotent & Multipotent Stem Cells:
- Totipotent cells: Toti means whole. These cells have high potential to give rise to any type of cells including somatic cells and mostly found in fertilized eggs (at very early stage).(ref) These cells are very easy to isolate and culture, but destruction of a human embryo is involved thus ethical issue related controversies are the biggest concern for the research use.
- Pluripotent cells: Pluri means many. These cells have comparatively less potential than totipotent cells. These are true stem cells and can differentiate into almost all tissue types. It is this feature that makes an identifying hallmark for human pluripotent stem cells (hPSCs). Embryonic Stem Cells (ESC) are pluripotent in nature. The ethical issues & teratoma formation (benign tumour) are the main concern for using these cells for the research purpose.
- Multipotent cells: Very low potency in comparison with previous categories. These are also true stem cells but differentiate into a limited range. Hematopoietic stem cells (HSC) and mesenchymal stem cells (MSC) are multipotent types. No direct human embryos are involved in this type of stem isolation hence less ethical issues are involved
Types of Stem Cells
There are mainly 3 types of stem cells:
- Embryonic stem (ES) cell: They can differentiate into any type of cell and mainly develop into germ layers;
- Ectodermal stem cell – transform to epidermis or skin cell, neurons & pigment cells.
- Endodermal stem cell – transform to specific organs.
- Mesodermal stem cell– transform to mesenchymal & hematopoietic stem cells.
- Adult stem cells: They can divide by self-renewal mode as well as give rise to specialized type of tissue/organ and show repair mechanism. They are less replicative than ES.
- Induced pluripotent stem cells (iPSCs): They are genetically reprogrammed adult pluripotent stem cells showing much similarities with ES. Human iPSCs express stem cell markers.
Human Embryonic Stem (ES) Cells’ – Why are they so important?
Human embryonic stem cells (hESC) is a very important research area due to its unlimited potential (both self-renewal & pluripotency)(ref1)(ref2) to form any type of body cell, suggesting the new opportunity in therapeutic medical research. At early embryonic phase the cells show totipotent capacity. The blastocysts (inner cell mass of 5 days old embryo) is a rich source of pluripotent ES cells. ES research shows growing interest on stem cell based engineering (tissue engineering) and regenerative medicines field(ref)7
Limitations of Embryonic Stem Cells Therapy
Despite of having enormous therapeutic advantages, ES in research has high ethical & political controversies.
- Involvement of the embryo is the major concern. Blastula staged embryo (~100 cells) which is normally isolated & grown in the fertility clinic; is the main requirement for research field or clinical trials. The blastula is very premature early stage of human life hence the debate; whether to consider blastula as unborn child or not. Although in vitro cultured blastula cannot develop into a fully grown child until implanted to the womb.
- Highly potential ES cells often show teratoma (tumour) formation during transplantation research trial indicating developmental abnormalities and ethical concern.
- Patient compatible ES cell lines creating are the biggest challenge as cells are collected from developed embryo.
- Prolong culture duration (in-vitro) decreases pluripotency capacity and develops chromosomal abnormalities
Adult Stem Cells’ – Importance over ES
Adult stem cells research is also of great interest as they are found in many tissues. Adult hematopoietic (blood-forming) stem cells of bone marrow, have been the main source as the transplant medical treatment for many years especially for leukaemia (blood cancer). Adult stem cells are also known as Somatic Stem Cells (SSC) & germline stem cells (gametes forming). SSC can remain in quiescent or undifferentiated state for long but divide when require, to replace the dying/damaged cells in diseased condition.
Adult stem cells can be collected/isolated from different tissues like
- Bone Marrow:
- Hematopoietic stem cells (HSC)
- Mesenchymal stem cells (MSC)
- Blood (Hematopoietic cell)
- Heart, Skin, Gut, Skeletal Muscles, Adipose or Fat tissues
Why Hematopoietic stem cells (HSCs) are the main focus in Stem Cell therapy?
HSCs are blood forming cells (through haematopoiesis process) and are mainly found inside the bone marrow (major site); although peripheral blood (small amount) & cord blood are also good source. Its unique ability for both self-renewal & multi-potency have giving them importance in the research field. HSC transplantation is very well established treatment process for genetic and acquired diseases like haematological cancer, autoimmune disease & hematopoietic disorders
What is Bone Marrow (BM)
Bone Marrow is the soft tissue inside bones. It produces RBCs, WBCs & platelets. It plays an important role in cancer stem cell therapies.
What is bone marrow transplantation (BMT)?
Bone marrow transplantation (BMT) is the well-known application in process of Stem Cell Therapy to treat hematological cancers, genetic disease etc. BMT can restore cells that are damaged due to chemotherapy or radiation therapy.
Stem cell transplant (complex process) is suggested when BM doesn’t work in its regular manner to produce sufficient functional stem cells. Cell transplant means infusion of good quality stem cells inside the body, so that enough healthy WBC, RBC & platelets remain within the body system.
Mainly 3 types of transplants are seen in the treatment procedure:
- Autologous transplants: involves own stem cells. [eg : SSC, iPSC]
- Allogeneic transplants: mainly donor stem cells [eg : ES, SSC, iPSC]
- Syngeneic transplants: Stem cells from identical twin.
Alternatives to BMT in Stem Cell Therapy?
- Peripheral blood stem cell transplant (PBSCT) is an alternative option of BMT. Bone marrow collection is a painful process. A survey showed that donors are more comfortable to donate peripheral blood stem cell (PBSC) compare to bone marrow and the ratio almost was 90:10. (ref)
- Another rich source of human stem cells are amniotic fluid/sac, placenta of pregnant woman and the blood of the umbilical cord (rich source of HSC). These stem cells can multiply faster than other sources. These tissues are normally discarded after the delivery of a child, so these can be considered an easily accessible non-controversial source of stem cells.
- Amniotic fluid: A good source of fetal stem cells (mesenchymal or tissue specific stem cells) most commonly use to confirm genetic defects or chromosomal abnormalities in fetus (amniocentesis). This stem cell source gives a new hope on medical research field, as the tissues are genetically matched with baby.
- Placenta : This is a maternal-fetal organ (unique temporary organ) and good source of stem cells (hematopoietic progenitor) during fetal development. Placental blood contains a high amount of unique stem cells (more immature stages) as compared to cord blood and known as perinatal stem cell.
Applications and advantages of Placental stem cells :
- Using human term placental tissues have less ethical controversies as this is considered as biological waste, and minimum costs are involved to obtain the tissues.
- Placental MSC lacks expression of human leukocyte antigens class II and other co-stimulatory factors which is giving these cells importance in allogeneic transplantation and therapeutic approaches. (ref)
- Placental cells have very limited scope to be exposed to the infections; hence less chances of disease transmission scope
- Umbilical cord blood: The rich source of hematopoietic stem cells (HSCs). Cord blood transplants showing hopes in the children with Fanconi anaemia (inherited genetic disease affects bone marrow function).
Read more on Umblical Cord Blood Banking
Mesenchymal Stem Cells
Bone marrows are the rich source of MSCs; although there are few other different sources (eg: adipose tissue, placenta, amniotic fluid and umbilical cord blood). MSCs are multipotent in nature and having self-renewing capacity. MSCs are characterised as follows:
- Repair mechanism ability and travel down to the site of inflammation.
- Produce compounds for the cell survival and division.
- Stops auto-immune responses.
Induced Pluripotent Stem Cells (iPS)
iPS can be generated or created directly from the adult somatic tissues. iPS shows huge similarities with ES but not exactly same. It’s a reprogrammed pluripotent somatic stem cells showing high therapeutic potentiality. In 2006, Shinya Yamanaka first shown iPS technology and awarded Nobel Prize (2012). The cell line they named as induced pluripotent stem cells (iPSCs) (ref)
Donor Cells for iPSCs
- Skin cells
- Frozen Blood cells
- Dental Tissues
- Cord blood
Applications of iPSC
- Drug development
- Regenerative medicines
Advantages and Limitations
- iPS are very interesting focus in the research field as the reprogrammed cells (transcription factors incorporated) are generated from adult somatic cells hence human embryos or oocytes are not involve. As a result less ethical issues are involved Skin biopsy is the non-invasive procedure to get somatic stem cell hence involve less risk. iPS cells are mentioned as “ethically unproblematic and acceptable for use in humans” by ‘The President’s Council on Bioethics “
- iPS share similar or equivalent cellular properties with ES and iPSCs (cell lines) have the potentiality to form fully differentiate tissue like ES.
- The germ cells (ectoderm, mesoderm, endoderm) can be differentiated from iPS.
- iPSCs show an enormous opportunity in human cancer biology
- iPSC although shows huge medical treatment opportunities, tumorigenicity and genomic instability are the biggest concern. Overexpression of oncogenes is the risk while using this cell lines (ref)
Ethical Issues in India on Stem Cell Isolation
India is religious country and every technology that involves humans is bound to draw ethical criticism. To regulate the working of stem cell therapy industry, Guidelines for ‘Stem Cell Research & Therapy’ were issued in 2007 by ICMR-DBT, specifying research ethical principles and committee approval processes on stem cell work and the periodic monitoring.
In 2014, revised guidelines were published by ICMR-DBT. Drug Controller General of India (DCGI) also support them for ‘stem cells and cell-based products.’
There are chances of misuse or exploitation of stem cell therapy or related research. Without adequate research data and safety guidelines; vulnerable patients’ exploitation is the biggest concern; hence revised guidelines of “The National Guidelines for Stem Cell Research (NGSCR)-2017” has been incorporated.
Risks involve in ‘Stem Cell Therapy’
Potential differentiation capacity of the stem cells has given them a unique place in research field; but unfortunately, there are few downsides too.
- Uncontrolled dividing capacity is the biggest risk for tumour formation. Teratoma formation is becoming a “gold standard” marker in stem cell research to assess pluripotency ability to overcome stem cell tumorigenicity related complex risks for patients.
- The stem cell lines are used during stem cell therapy and there are chances of contamination or infection, in case infected cell lines has been transferred (ref)
- Without proper standardized data and safety precaution stem cell therapy can be risky for the patients
- Immune system is crucial to maintain total body integrity. If the immunity gets disturbed, it acts on own body defence mechanism and fight against each other (autoimmunity). This autoimmune disease is the real problem in medical science as the transplanted organs are rejected by the body’s own immune system (graft-versus-host disease)
Stem cell therapy has an exciting future in medical treatment field. Organ regeneration/repair will be a focusing area in healthcare industry. Human cloning technology related ethical issues & legal obstacles need to be sorted out for better outcome on therapeutic cloning
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