Abstract
Mesenchymal stem cells (MSCs) can differentiate into endoderm lineages, especially parathyroid-hormone (PTH)-releasing cells. We have previously reported that tonsil-derived MSC (T-MSC) can differentiate into PTH-releasing cells (T-MSC-PTHCs), which restored the parathyroid functions in parathyroidectomy (PTX) rats. In this study, we demonstrate quality optimization by standardizing the differentiation rate for a better clinical application of T-MSC-PTHCs to overcome donor-dependent variation of T-MSCs. Quantitation results of PTH mRNA copy number in the differentiated cells and the PTH concentration in the conditioned medium confirmed that the differentiation efficiency largely varied depending on the cells from each donor. In addition, the differentiation rate of the cells from all the donors greatly improved when differentiation was started at a high cell density (100% confluence). The large-scale expression profiling of T-MSC-PTHCs by RNA sequencing indicated that those genes involved in exiting the differentiation and the cell cycle were the major pathways for the differentiation of T-MSC-PTHCs. Furthermore, the implantation of the T-MSC-PTHCs, which were differentiated at a high cell density embedded in hyaluronic acid, resulted in a higher serum PTH in the PTX model. This standardized efficiency of differentiation into PTHC was achieved by initiating differentiation at a high cell density. Our findings provide a potential solution to overcome the limitations due to donor-dependent variation by establishing a standardized differentiation protocol for the clinical application of T-MSC therapy in treating hypoparathyroidism.
Highlights
The parathyroid gland is an endocrine organ that dynamically secretes parathyroid hormone (PTH) as a polypeptide consisting of 84 amino acids, in response to changes in extracellular calcium concentrations, regulating ion homeostasis [1]
The differentiated T-MSCPTHCs embedded in a Matrigel restored in vivo parathyroid function [18]
We demonstrated that T-Mesenchymal stem cells (MSCs) differentiated into parathyroid tissue spheroids and confirmed that the tonsil-derived MSC (T-MSC)-PTH-Releasing Cells (PTHCs) spheroids were highly viable (>80%); they expressed
Summary
The parathyroid gland is an endocrine organ that dynamically secretes parathyroid hormone (PTH) as a polypeptide consisting of 84 amino acids, in response to changes in extracellular calcium concentrations, regulating ion homeostasis [1]. Hypoparathyroidism causes low serum calcium and high serum phosphorus levels, as well as inadequate/deficient PTH secretion [2,3]. The most common treatment for this condition is hormone replacement therapy with calcium and vitamin D, but this may not be sufficient to compensate for the loss of endocrine function. Allografts are a good way to treat patients who are unable to receive autograft treatment, but this has limited success due to the side effects associated with tissue rejection [4]; MSC therapy as a treatment for hypoparathyroidism is expected to be used clinically in the future
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