Recent concepts in stem cells transplant.

Stem cells = cells having the ability of self-renewal & differentiation. They are classified according to the type of differentiated cell they could b

Recent concepts in stem cells transplant.

 

Stem cells 👉 cells having the ability of self-renewal & differentiation. They are classified according to the type of differentiated cell they could be reproduced. Pluripotent stem cells can develop ALL embryonic cells, that include germ cells & other cells developed from ectodermal, mesodermal, & endodermal germ cell lines.

 

Embryonic stem cell is typically emerged from a 👉pre-implantation blastocyst (7-10 d after fertilization). Adult stem cell is typically derived from tissue formed after 10-14 d after fertilization that is usually called "somatic" stem cells if derived from non-germ cell tissue. It’s not evident if adult stem cells are present in all types of tissues, e.g., pancreatic islet cells.  By year 2006, it could be possible to develop induced pluripotent stem (iPS) cells via "re-programming," a technique that involves gene transplantation (Tx) into mature cells, with reversal into a pluripotent state. Development of iPS cells can supply the potential for using tissue culture to develop a specific tissue derived from a totally other somatic cell. Potentiality of therapeutic applications is so great, despite the current need for genetic manipulation may limit the wide clinical applications.  

 

Examples using human ES cells: Human embryonic stem (ES) cells have been successful differentiation in vitro into various cell types for therapeutic purposes, e.g.,👉

1)    Oligodendrocyte,

2)    Pancreatic cell,

3)    Cardiomyocyte,

4)    Motor & dopaminergic neurons, &

5)    Hematopoietic precursor cell (s).

Therapeutics for ES cell-derived somatic cell has been shown in animal trials of retinal blindness, Parkinsonism, Huntington dis, spinal cord lesions, MI, & type I DM.

Retinal disease: Human ES cell-derived retinal photoreceptors was used to improve visual acuity in blind mice. After intraocular injection, retinal cells taken from human ES cells can migrate into the specific retinal layers & expressing rod & cone photoreceptor Sub-retinal tx of the cells into the sub-retinal space of mice with congenital amaurosis have restored their light response. Study: ES cell-derived photoreceptors tx into mice eyes can mature into specific photoreceptors.

 

Parkinson disease: An enriched cohort of mid-brain neural stem cells was derived from mice ES cells. Dopamine neurons that were developed via these stem cells showed electrophysiologic (EP) & behavioural criteria expected from neurons from the midbrain. These ES-derived neurons can be survived after tx into rats with Sms of Parkinsonism with better EP properties & alleviated lesional movements. So, functional improvement was seen with the use of human ES cell-derived dopaminergic neurons after tx in a Parkinsonian rat model. Moreover, tx of differentiation stage defined ESC-derived neuronal progenitors leads to dopamine neuron engrafting with strong induced recovery of the motor lesions in a hemi-parkinsonian mouse.

Huntington disease: Degenerated neuronal gamma-aminobutyric acid (GABA) in the basal ganglia may underly motor dysfunction in Huntington dis. (HD). Human ES cells differentiated into the fore-brain neuronal GABA were tx into the brains of mice in an HD model. These ES-cell-derived neurons can replicate the substantia nigra, receive glutamatergic & dopaminergic inputs, with restored motor neuron function.

Spinal cord (SC) injury: Tx of human ES-derived oligodendrocyte progenitor cells into adult mice, 7 days after inducing spinal cord injury, was shown to trigger re-myelination & induce improved motor function. Tx cells can survive, redistribute, and differentiate into oligodendrocytes, showing a therapeutic potential after recently induced SC injury.

Myocardial infarction (MI) & HF:  An investigated Safety/efficacy of ES-based therapy in acute MI or ischemic CMP still lacking an evidence of therapeutic potential. 

DM type I: An efficient direct differentiation of human ES cells to insulin-providing pancreatic beta cells is currently achieved. They have:

1)    Expressing key markers of mature pancreatic beta cells,

2)    Providing glucose-stimulated insulin production like adult beta cells; &

3)    A human insulin can be secreted into serum of mice immediately post-transplant in a glucose-regulating manner, alleviating hyper-glycemia in the diabetic mice.

Clinical uses of human ES cells: By 2015, 1^st phase study reported on safety & tolerability of human ES cell use for ttt retinal disease; this involved 9 ptns with dry age-related degenerated macula & another 9 with Stargardt's macular dystrophy. Human ES cell differentiation leads to 👉 99 % pure retinal pigment epithelium (RPE), of which 50,000-150,000 RPE cells were injected into subretinal space. Graft survival was shown by an increased subretinal pigmentation with tx retinal pigment epithelium. Ptns were ttt with low-dose tacrolimus + MMF for im/m. starting one wk prior to procedure and continues for 6 wks, followed by more 6 wks of MMF alone. There was no evidence of adverse proliferation, rejection, or serious ophthalmic or systemic safety issues in relation to tx tissue with  22 mo follow-up. Improvement in visual acuity 😄 was observed in the injected eye in 10 of 18 ptns.  😨

Next studies exploring tx of human ES cell derived RPE cells in a degenerated macula were confirming safety + clinical benefits in small quantity of ptns. Other uses of human ES-based cellular ttt has been reported in ptns with severe ischemic LV dysfunction. Human ES cell-derived CVS progenitors in a fibrin patch were tx into the epicardium via coronary artery bypassing in 6 ptns. Technically feasible was the production of clinical-grade human ES cell-derived CVS progenitors as well as short/medium-run safety, that opens the way for more efficient trials. Additional studies concerned with the doses, efficacy, & safety profiles in a wide spectrum of ptns are warranted before widespread applications of human ES cell tx. Spectrum of diseases with ES-cell based ttt is expected to expand. Clinically, ES-derived cell components have been commenced in 👉 (1) spinal cord injuries, (2) type 1 DM, & (3) amyotrophic lateral sclerosis.

 

Technology-related considerations may include: 👉

1)    Oncogenic risk of the tx material,

2)    Integrated tx cells into a complex cell network, &

3)    Generation of the desired target cell type within the proper stage of differentiation.

Stem cell tx own the capability to alter diseased tissue in a 👉paracrine fashion, with no true engraftment. Medications directed to the endogenous stem cell can alter its response to injury. Lastly, stem cells may generate tissue to be used as lab models for the disease studying where obtaining live tissue is otherwise difficult or not possible. Ethically wise, there’re many concerns regarding stem cell workup. Utilizing induced pluripotent cell (s) may alleviate many concerns related to embryo disruption, however, many other concerns still unanswered.