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Research progress and challenges of three different stem cell transplants for the treatment of acromegaly!

by Zeev Lo Va 2 months ago in science
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Stem cell therapy for acromegaly

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Atrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons.

The pathogenesis and progression of ALS are still unclear, and there is no effective treatment to stop or reverse ALS.

In recent years, stem cell transplantation has provided new ideas for the treatment of ALS. Several early clinical trials evaluating the potential of stem cell transplantation for ALS have been initiated, and stem cell transplantation may be a viable option for maintaining and culturing motor neurons.

Stem cell-based therapy is currently a hot research topic in the treatment of neurodegenerative diseases. Cell therapy replaces degenerated or dead neurons by transplanting new neurons, allowing stem or progenitor cells to differentiate in some way into the desired cell type in vivo.

The preclinical trials of different types of stem cells for ALS are described separately.

Mesenchymal stem cells

MSCs transplantation has been demonstrated in animal model experiments and human trials as a therapeutic option for a variety of tissue and organ diseases, including ischemic brain injury and neurodegenerative diseases.

Currently, there are no reports of adverse effects associated with phase I trials of intrathecal and intravenous bone marrow MSCs (BMSCs); in addition, trials related to the injection of adipose-derived MSCs have been safer.

Basic research on mesenchymal stem cells

It was shown that transplantation of human or rodent-derived MSCs into standard SOD1 mutant SOD1G93A mice significantly improved motor function and prolonged lifespan, with better motor activity and motor function, slower weight loss and longer mean lifespan in the extremities of the MSCs group compared with the 0.9% NaCl injection group [1].

Clinical cases

Some scholars divided 37 BMSCs transplanted ALS patients into two groups, "responders" and "non-responders", and showed that the former had a significantly smaller decrease in ALS functional scale scores [2].

Another study used differentiated BMSCs in culture to enhance the secretion of neurotrophic factors and administered these cells intramuscularly combined with intrathecal injections to 14 patients and showed a reduction in ALS functional scale scores and exertional spirometry during the 6-month follow-up period after BMSCs transplantation compared to the 3-month pre-transplantation break-in period [3]. This suggests that the transplantation of BMSCs may improve clinical symptoms in ALS patients.

MSCs transplantation may work by prolonging the survival time of damaged motor neurons and preserving existing motor circuits, which can be achieved in several ways.

1. Paracrine effects of MSCs secreting neurotrophic factors

Human umbilical cord MSCs can secrete six different neurotrophic factors: brain-derived neurotrophic factor, nerve growth factor, neurotrophic factor 3, vascular endothelial growth factor, insulin-like growth factor-1, and glial cell-derived nerve growth factor (GDNF), which can be secreted individually or in combination to promote the survival of diseased motor neurons in a paracrine manner.

2. Immunomodulatory effects of MSCs on peripheral blood T cells

When MSCs were co-cultured with peripheral blood mononuclear cells from ALS patients, the levels of anti-inflammatory cytokines such as gamma interferon, interleukin-4, and interleukin-10 increased, and Treg cell induction was enhanced; moreover, the immunomodulatory capacity of MSCs was mediated by Toll-like receptors that are intrinsically immune-mediated. Therefore, as peripheral immune cells infiltrate into the CNS, the Treg cell potential induced by MSCs transplantation becomes particularly important.

3. Potential modulation of glial cell-mediated neuroinflammation by MSCs

In addition to peripheral immune cells, MSCs can also modulate the intrinsic immune response of glial cells in the CNS. Non-neuronal cell autonomic factors are important pathological features of ALS, while central glial cells play a crucial role in the death of motor neurons.

Neural stem cells

Neural stem cells may provide neurotrophic support and replace glial cells or interneurons and may exert neuroprotective effects by secreting a variety of molecules and growth factors. ALS-related trials using human embryonic tissue-derived neural stem cells expanded in culture have been conducted in Europe and the United States.

Basic neural stem cell research

After transplantation of fetal cortical-derived NSCs into the spinal cord of ALS model SOD1G93A rats, the NSCs were able to differentiate into neuroprotective astrocytes; if the NSCs were genetically modified to produce GDNF, they had beneficial effects on the motor neurons of ALS model SOD1G93A rats, which not only delayed the onset of ALS model SOD1G93A rats, prolonged their survival, and improved the upper motor neuron It can not only delay the onset and prolong the survival time of SOD1G93A rats, but also improve the health status of upper motor neurons, and even increase the survival rate of spinal motor neurons in ALS model SOD1G93A rats [6].

It was demonstrated that the atrophic spinal cord of ALS patients could tolerate at least 3 mL of cell suspension and up to 20 injections of different spinal cord segments, and no tumor growth was detected at a 2-year follow-up after transplantation of NSCs [7]. It is evident that NSCs transplantation did not accelerate the disease progression of ALS and that NSCs transplantation in ALS patients is relatively safe and feasible.

Embryonic stem cells

Human embryonic stem cells (hESCs) are primitive pluripotent stem cells derived from the cell mass in human blastocysts, which are isolated and cultured in vitro.

Basic research on embryonic stem cells

Izrael et al [8] further investigated animal models of ALS (high copy number hSOD1G93A transgenic mice and rats) and found that intrathecal injection of his-AS significantly delayed the onset of ALS in hSOD1G93A mice and rats and contributed to the maintenance of motor function and delayed death; similar to normal astrocytes, hESCs could protect motor neurons through various mechanisms, such as scavenging glutamate. motor neurons, such as scavenging glutamate, secreting multiple neuroprotective factors, neutralizing reactive oxygen species, and promoting nerve growth.

Compared with the blank carrier solution control group, the hESCs-treated rats maintained normal locomotion for more than 1 month; the median survival of the hESCs-treated rats was 216 d, compared with 182 d in the control group, indicating that intrathecal injection could delay the onset and disease progression of ALS and thus prolong the survival.

All of these studies confirm the feasibility, safety, and potential efficacy of intrathecal injection of hESCs for the treatment of ALS.

Summary

Preclinical studies with stem cells have laid the groundwork for human trials to differentiate stem cells into cells with therapeutic potential, revealing possible mechanisms to slow neurodegeneration by improving the toxicity of the disease microenvironment.

Among the proven safe stem cell sources, identifying the most effective stem cell source, dose, site, and method of administration are important to further improve the efficacy of stem cell transplantation therapy. Stem cell transplantation has great potential for use in the treatment of ALS and other neurodegenerative diseases, but stem cell-based therapies still require considerable research.

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About the author

Zeev Lo Va

Who to idle away one's time, youth will fade, life will abandon them。

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