Stem Cells & Stem Cell Transplantation

Stem Cells and Stem Cell Transplantation.

                      PKGhatak,MD

 

Stem Cells and Stem Cell Transplantation.

The total number of cells in a human body is unknown. It is estimated that an adult average person has 34 trillion cells, about 200 different cell types. The cells perform a multitude of functions. However, one group of cells is assigned only one bodily function, take for example - liver cells are assigned protein manufacturing, whereas, kidney cells filter blood and discard the waste product as urine. Each cell has 23 pairs of chromosomes, (sperm and ovum just one copy), and the genes of the chromosomes carry the blueprints of cellular functions. The question then arises, who decides the type of function a cell should perform and who is watching over. Why not one day the liver cells start producing urine like kidney cells. Molecular biologists and bioengineers are gradually unlocking those secrets and applying their knowledge in creating new exciting chapters in human biology.

In every organ, there are primitive cells that have retained the embryonic property, namely, the capacity to produce several lines of cells. Stem cells are also distinct in another way from mature cells- they can replicate themselves and produce mature cells at the same time.  These cells are the mother of all cells and jack of all trades and are called Stem Cells.

We have three distinct types of stem cells.

1. Embryonic Stem Cells are also called Pluripotent Stem Cells. They can turn out any line of cells.
2.The second type of stem cell - the Induced Embryonic Stem Cell. Scientists make them in laboratories from Adult Stem cells (not to be confused with the cells from an adult person). Induced embryonic stem cells function the same way as regular embryonic stem cells.

3. And the third group is the Adult Stem Cells. They are present in all tissues, organs and peripheral blood. But each adult stem cell is limited to generate just one line of cells. These cells are named according to their place of origin, for example - Mesenchymal stem cells originated in embryonic mesoderm, and Hematologic stem cells originated in the bone marrow. 

Additional sources:

A. There is an additional source of stem cells from cord's blood and blood in the placenta. Cord stem cells are able to cross the blood brain barrier. Another advantage of cord stem cells is that they do not produce significant adverse immune responses in recipients.

B. Scientists are capable of engineering the Embryonic stem cells to become Progenitor cells then turn them to precursors to adult stem cells and finally to mature cells. They can reverse the process and make the Embryonic stem cells from the adult stem cells. Scientists also know how to coax the bone marrow and other tissues to release stem cells in the peripheral blood. 

C. Scientists can clone human embryonic stem cells in the laboratory from an unfertilized egg, they first remove the nuclear material and replace it with the nuclear material from a cell of a patient waiting for stem cell transplant. This engineered egg cell then advanced to a Blastocyst and was guided to become an embryonic stem cell and finally into adult stem cells.

                                                            Transplantation:

The sold organ transplants began with a cadaver kidney transplant in 1950 in France. In 1954 a kidney transplant was successfully performed in Boston, MA using a kidney from a living donor.

In 1956 a Bone marrow transplant was performed in New York. A leukemia patient received a bone marrow transplant from his twin brother. These successes encouraged bone marrow transplantation. Now it has become a standard therapy in Leukemia and related conditions.

Bone marrow transplants for non-cancerous blood conditions are a natural extension of that success.

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Some confusing terminology.

Allo -means the other person or not genetically identical. Auto - means from one location to another in the same person. Autologous- means tissue obtained from the same person. Syngeneic - means biologically similar or identical. Homeostatic - means inert like bone and cartilage.

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Basic Consideration for stem cell transplant.

Stem cell transplantation is not risk free. In allogeneic transplants, the donor ABO blood group and HLA tissue group must match with recipients' and thus the availability of donors becomes a big hurdle. Several life-threatening complications, both prior and post transplants, must be avoided. Immune reactions may lead to graft failure and graft versus the host disease as seen in solid organ transplants. 
 [ It should be kept in mind that stem cells are modified in the laboratory to match a particular organ or tissue requiring a transplant. ]

Bone marrow  failure is the most often reason for for stem cell transplantation in Non - malignant condition. and the second group is chemotherapy and radiation therapy induced bone marrow depression.

 A. Stem cell Transplantation for Non-malignant diseases:

 1. Aplastic Anemia.   In aplastic anemia, the Hematopoietic stem cells fail to produce adequate numbers of Red Blood cells (RBC), WBC (white blood cells) and Platelets. Anemia becomes very profound.

2. Other conditions lead to Aplastic anemia. - Radiation injury to bone marrow as documented in atomic bombs survivors in Japan.

3. Accidents in atomic power plants result in the leakage of radioactive gases and water into the environment.

4. Excessive radiation exposure to techs and doctors in the radiology department of hospitals.

 5. .Intentional or accidental poising with radioactive agents. 

6.Thalassemias, paroxysmal nocturnal hemoglobinuria.

7. Sickle cell anemia. Heavy metal poisoning, exposure to benzene and gasoline byproducts.

8.Viral infections - it includes HIV, all hepatitis viruses, specially, Hep B and Hep C. Epstein-Barr virus, Parvoviruses, Cytomegalovirus.
Recent COVID-19 pandemic some sick patients were found to have depleted beneficial immune cells and mesenchymal stem cell transplantation to replace immune cells is undergoing trial in some centers.
9. Diseases like Lupus, Rheumatoid arthritis.
10.Drugs - many drugs are known to produce bone marrow depression, these drugs are numerous, starting from chloramphenicol to phenylbutazone. 
11. Several congenital immunodeficient diseases - Fanconi anemia, Diamond-Blacklane syndrome, Schwachman Diamond syndrome.

Since the patient's own hematopoietic stem cells are nonfunctional, a bone marrow transplant, either from a matched donor or matched cord blood (Allogenic) stem cell transplant is performed. This procedure is called Allogenic hematopoietic stem cell transplantation.

 Experimental Stem cell transplantation.

1.Neurological diseases:  Stem cell transplant, initially, was enthusiastically welcomed as the lifesaver for Parkinson's disease. Alzheimer disease. Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), Spinal cord injuries, and Strokes. Neurogenic stem cells and Cord Blood stem cells were used. But long term results were disappointing. At present stem cell transplantation in neurodegenerative diseases is considered experimental. Similarly, spinal cord injury cases are abandoned. 

2. Heart diseases:  Damaged heart muscles can be repaired by injecting mesenchymal stem cells directly into damaged muscles in experimental animals. A few years later similar stem cell transplants were performed in the post MI heart failure patients. Stem cells were given IV. Heart specific adult stem cells and mesenchymal stem cells were used. Now, such procedures are considered experimental because of frequent complications.

 3. Liver diseases: Stem cell transplants are performed on varieties of liver diseases, the most frequent among them are Alcoholic cirrhosis, Non-alcoholic cirrhosis, Alpha 1 antitrypsin deficiency, Autoimmune liver diseases, Galactosemia, Hemochromatosis. Wilson's disease, Gilbert syndrome. The initial enthusiasm now has subsided because of frequent failures. It is relegated as experimental. 

4. Wound repair: The skin is rich in mesenchymal stem cells. These stem cells are used in various types of wounds to speed up the healing and repair of ligaments, cartilage and bones.

 5. Juvenile Diabetes: Juvenile diabetes is due to autoantibodies attacking the Beta cells of the pancreas, resulting in Insulin deficiency. Engineered beta cells are transplanted and done. Initial results are encouraging. 

Malignant condition:

 A. Patients with Hematological Malignancies are good candidates for stem cells transplants:
Acute Myeloblastic leukemia (AML), Acute Lymphoblastic Leukemia (ALL) and Chronic Myelocytic Leukemia (CML) happen due to the translocation of genes known as the Philadelphia chromosome.  Allogeneic hematopoietic stem cell (from a donor) transplantation produces good results and promises a cure. Donor stem cells are needed because the malignancy involves the hematopoietic stem cells of patients.

B. Multiple Myeloma: The disease is a malignancy of the Plasma cells.  Autologous hematopoietic stem cell (stem cells harvested from the patient) is done. It is considered curative therapy.

C. Lymphoma, Lymphosarcoma, Mantle cell lymphoma, Non-Hodgkin Lymphoma, myelodysplastic syndrome is treated with Autologous hematopoietic stem cell transplants following initial chemoradiation, in cases of recurrence.

D. Ewing Sarcoma: This childhood bone sarcoma is due to a translocation of genes between chromosomes 11 and 22. After a relapse following chemo-radiation therapy Autologous hematopoietic stem cell transplantation is generally performed.

D. Solid organ malignancy:

  At one time it was thought to be an answer to advanced solid organ cancers. The hematopoietic stem cells are harvested from the bone marrow of the patient first in the preparation for stem cell transplant, then the patients are subjected to a very high dose of chemotherapy agents followed by whole body radiation and the head, to eliminate every possible cancer cells. Then Autologous stem cell transplant is performed.
The results are not very encouraging at present; this is relegated to the experimental status.

[ Malignancy of the solid organs treated with chemotherapy and radiotherapy often causes severe bone marrow depression. Allogeneic hematopoietic stem cell transplants are performed to replace them.]


Perils of Stem cell Transplantation:

1.The transplant may fail to take hold and ultimately fail.
When patients' immune system is severely depressed the patients become very vulnerable to infection by every kind of infectious agent, including reactivation of previous virus illnesses and tuberculosis. 2. 2. After a transplant, it takes time for the body to replenish the immune system and the patient still remains vulnerable to infection. 
3. Rejection of graft (stem cells) by the recipient.
4. Graft versus Host disease: Here the graft tissue (transplanted stem cells) attacks the host's cells and damages various organs and tissues.

These anticipated complications are well known to the transplant centers and proper treatment protocols are in use. It should not be a major concern to needy patients.

Ethical issues. It began in earnest when cloned of human stem cells were produced in the laboratory. At present the clone stem cells are not used in transplants. Stem cells are obtained from the patient's peripheral blood or from their bone marrow and also from donors. But still, it generates debates among the concerned population.
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