الفهرس 
Aim of the workOnly 14 pages are availabe for public view
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Abstract
1- Optimizing cellular therapy for DMD may need the following:
- huge number of functional and mature myogenic progenitor cell ready to fuse to form myotubes and keep myogenic progenitor stem cells pool.
- immunomodulation of host skeletal muscle so possibility of cell rejection decrease.
- Supply of sufficient amount of growth factors necessary for survival and differentiation of myogenic cells in vivo.
The combined cellular therapy or Co-transplantation approach may provide all above-mentioned factors to treat muscular dystrophies. The co-transplantation of myogenic progenitors cells and MSCs or MSCs related products as cytokines can decrease the severity of the primary and secondary pathological pathways underlying DMD, myogenic progenitors cells will provide the muscle tissue with normal muscle fibers containing dystrophin protein and
In the same time MSCs will provide the transplanted myogenic cells with healthy non-hostile environment surrounding them upon transplantation (by their paracrine growth factors secretion, immunomodulatory and antifibrotic functions) facilitating their migration , survival, proliferation and engraftment inside host muscle tissues and decrease the need for large number of transplanted myogenic cells..
2- More researches have to be conducted on role of managing secondary pathological mechanism related to DMD.
When we have to start fighting these mechanisms is important. Every day scientists make new step toward discovering cure for DMD by targeting its primary cause (dystrophin deficiency) but we don’t know will these therapeutic approaches will be beneficial if the secondary pathological mechanism is irreversible so may be management of these ongoing pathological mechanisms is mandatory for treating DMD.
Mesenchymal stem cells may be a tool for controlling these secondary pathological mechanisms by their wide diverse abilities.
3- For the co-transplantation approach which is the best method suitable for delivering (I.M or I.P) mesenchymal stem cells with myogenic cells?
We think that local administration of MSCs may change their phenotype into fibroblastic type, in a previous study investigated the role of bone marrow mesenchymal stem cell (BMSC) transplantation after muscle contusion. BMSCs were immediately transplanted into gastrocnemius muscles (GMs) following direct contusion (231). Comprehensive morphological and genetic analyses were performed after BMSC transplantation.
BMSC transplantation exacerbated muscle fibrosis and inflammation, as evidenced by increased leukocyte and macrophage infiltration, increased inflammatory cytokines and chemokines, and increased matrix metalloproteinases (231).
BMSC transplantation also increased muscle oxidative stress. Authors conclude that local BMSC transplantation aggravated inflammation, oxidative stress and fibrosis and impaired skeletal muscle regeneration (231).
So, may be the local I.M administration of MSC with myogenic cells will prevent successful engraftment of co-transplanted myogenic cells by increasing fibrosis and inflammation.
Also, we think that local administration of MSC with myogenic cells may compete with transplanted myogenic cells for blood supply and nutrients decreasing the ability and number of myogenic cells ready for engraftment and formation of new myotubes.
from our work we recommend I.P MSCs administration approach because it may have wide spread paracrine systemic effect affecting limb muscles, diaphragm and cardiac muscle and may avoid the damaging effect of local injection.
4- keep MSCs phenotype fixed in-vitro and in-vivo after transplanting them, this is a major concern because if mesenchymal progenitor cell change to the fibro/adipogenic phenotype for an example, this may add more damaging effect rather than a protective one.
So, learning how to keep the undifferentiated state of MSCs and monitor transplanted cell phenotype is an essential step before considering the co-transplantation approach a possible therapeutic approach for DMD.
This can be done in-vitro and in-vivo by observing cell morphology, trilineage differentiation potential, immunostaining for PDGFRα receptor levels and frequent genetic analysis for fibrogenic genes.
5- Using hiPSCs technology seems to be a promising co-transplantation therapeutic tool for DMD, with the ability of unlimited expansion of cells in vitro.
Deriving from the same matching donor or patient iPSCs both myogenic progenitor and mesenchymal progenitor cells may decrease the immune response and ongoing inflammatory process and increase the survival of myogenic cells ready for engraftment.
For DMD - hiPSCs therapeutic development proper derivation of mature myogenic cells and MSCs by development of efficient, safe induction techniques with phenotypic preservation of transplanted cells after injection with complete exclusion of teratogenicity is mandatory before hiPSCs cell based therapy.
This strategy could be a valuable therapeutic approach in the near future. So, improving the induction methods of MSC and myogenic cells from hiPSC is mandatory.
Developing of more efficient, short time and safe induction methods for mesenchymal stem cells is needed before application of the co-transplantation protocols a therapeutic tool for DMD.