Introduction (Draft)
Stem cell transplantation is a procedure that has been garnishing immense attention
these past few decades, since it is considered to be novel approach to the treatment of many
diseases. The preliminary goal of stem cell transplantation is to regenerate the repertoire of
stem cells that might have been ravaged by disease. It is also important to note the
transplantation eligibility when considering bone marrow transplantation.
Not all patients can withstand the conditioning regimen required for transplantation,
and the side effects of such a treatment since it relies on the use of chemotherapy agents
before transplantation. This can have adverse effects on the patient undergoing transplantation
treatment.
High-dosage treatment places great stress on the body and can cause damage to major
organs, this can be due to the intense chemotherapy required before transplantation.
Furthermore, major compromises to the immune system are expected to occur, this can cause
secondary infections to appear which might be fatal to the elderly population. All these factors
have allowed the theorization of a transplantation methodology without the incurring use of
chemotherapy or radiation therapy as a preliminary requirement for the transplantation of
bone marrow.
10.1111/ajt.14238 (Explains why chemotherapy is required for transplantation)
Chemotherapy is needed in part to mobilize stem cells from the bone marrow to make
room for the transplanted stem cells. The main issue with the usage of chemotherapy in
combination with a mobilizing agent is the fact that the immune system becomes
severely compromised, leading to the possibility of developing cancer or secondary
infections.
10.1016/j.blre.2014.01.001 (Mobilization Agents)
There exists several mobilization factors that can aid in stem cell mobilization from the
bone marrow, although few are considered as great candidates for increased efficacy of
mobilization.
GM-CSF is an example of a mobilizing agent that nowadays is rarely used for stem cell
mobilization from the bone marrow. An experiment was done to analyze the
mobilization capabilities of GM-CSF in comparison with G-CSF and what was discovered
was the fact that GM-CSF mobilized far fewer CD34+ cells as compared to G-CSF in
healthy subjects, but what was interesting about this experiment was the fact that GMCSF yielded higher rate of mobilization of CD14+, monocytes, dendritic cells, and T
regulatory cells as compared to G-CSF.
Plerixafor is a bicyclam molecule that reversibly inhibits SDF-1 binding to CXCR4,
increasing HSC mobility. This connection between SDF-1 and CXCR4 is crucial for HSC
quiescence and retention inside the bone marrow. Plerixafor is authorized for use in
conjunction with G-CSF to mobilize stem cells in myeloma and lymphoma patients.
For the purpose of autologous stem cell transplantation, chemotherapy is frequently
utilized to mobilize stem cells. The precise drugs selected are typically disease-specific
and are utilized to both lessen the burden of the tumor and improve mobility.
The most widely used chemotherapy drug, cyclophosphamide (CY), has undergone
testing at various doses.
BKT140: is a CXCR4 antagonist that when utilized has lead to a 10x increase in stem cell
mobilization, but when paired with G-CSF has led to a 64x increase in stem cell
mobilization.
NOX-12: is another mobilizing agent that binds to SDF-1 and can inhibit its binding to
CXCR4. This agent induced reversible mobilization of HSC and lead to successful long
term engraftment, combined with the usage of G-CSF.
Why G-CSF is Better?
G-CSF selectively mobilizes quiescent non-dividing hematopoietic stem cells from the
bone marrow to the blood. Another advantage of G-CSF is that the compound does not
induce the cycling/proliferation of HSC, which means that mobilized HSC can return to
the bone marrow without dividing. These non-dividing HSC represent the true repertoire
of stem cells in the bone marrow.
DOI: 10.1080/01926230390244924
Side Effects of G-CSF
Data pertaining to the side effects of G-CSF are generally well documented, with
the majority of documented research indicating that G-CSF has no major side effects, but
some must be taken into consideration.
These side effects include, but are not limited to, bone pain, fatigue, headache,
nausea, insomnia, myalgia, and even redness at the injection site. These symptoms can
be considered mild ones, and are easily remediated. However, some major
complications can occur, but these cases are extremely rare. The major complications
associated with an increased intake of G-CSF are acute lung injury, which might be due
to inflammation, splenic rupture, and the increase sensitivity of the immune system
response.
Mechanism of Action of G-CSF
To determine the mechanism of action of G-CSF, an experiment was done by
Greenbaum (2010), that focused on the receptor of G-CSF, which is termed G-CSFR. GCSFR is commonly found in mature neutrophils and monocytes. However, research has
shown that G-CSFR is also expressed by Hematopoietic Stem Cells (HSC’s). To determine
if G-CSFR plays an important role in mobilization, a series of bone marrow
transplantations were set up in mice to determine the viability of G-CSFR. Wildtype mice
and mice with G-CSFR gene knocked out were transplanted with HSC’s from the bone
marrow, and mobilization rates of HSC were monitored. Wildtype mice mobilized HSC’s
from the bone marrow normally, as expected, but mice with the knock-out G-CSFR did
not mobilize any HSC’s, this means that the G-CSFR receptor plays a critical role in the
mechanism of action of G-CSF mobilization.
C-Kit and Kit-Ligand also play a crucial role, with G-CSF, in HSC’s mobilization.
HSC’s located in the bone marrow express high levels of C-Kit and Kit-Ligand, the
administration of G-CSF cleaves C-Kit and Kit-Ligand into their soluble forms, the soluble
forms of these proteins are more commonly found in HSC’s that are mobilized, as
compared to HSC’s in the bone marrow which express high levels of C-Kit and Kit-Ligand.
The CXCR4 receptor in-conjunction with its ligand CXCR12 is also affected by GCSF administration. Research has been done to show that an increase of CXCR4 signaling
increases HSC’s retention in the bone marrow, where it is constitutively expressed.
When G-CSF is administered an initial rise in CXCR12 mRNA is observed, there is still no
conclusive results for the reasoning behind this but logically it might have something to
do with the activation of a negative feedback cascade, whereby an initial increase in
CXCR12 mRna, activates a negative feedback loop. After this initial rise in CXCR12, a
massive drop is recorded due to G-CSF, indirectly or directly, affecting the CXCR4/CXCR12
cascade, promoting increased mobilization of HSC’s from the bone marrow to the
peripheral blood.