Sustained release of parathyroid hormone via in situ cross‐linking gelatin hydrogels improves the therapeutic potential of tonsil‐derived mesenchymal stem cells for hypoparathyroidism

Abstract

Biomimetic parathyroid regeneration with sustained release of parathyroid hormone (PTH) into the blood stream is a considerable challenge in hypoparathyroidism treatment. We recently reported that tonsil-derived mesenchymal stem cells (TMSCs), if these cells were both differentiated in vitro before implantation and incorporated into a scaffold Matrigel, are a good cell source for parathyroid regeneration in a parathyroidectomized (PTX) animal model. Here, we present a new strategy for improved clinical application that enhances the sustained release of PTH by controlling mechanical stiffness using in situ-forming gelatin-hydroxyphenyl propionic acid (GH) hydrogels (GHH). Differentiated TMSCs (dTMSCs) embedded in a GHH with a strength of 4.4 kPa exhibited the best sustained release of PTH and were the most effective in hypoparathyroidism treatment, showing improved blood calcium homeostasis compared with Matrigel-embedded dTMSCs. Interestingly, undifferentiated control TMSCs (cTMSCs) also released PTH in a sustained manner if incorporated into GHH. Collectively, these findings may establish a new paradigm for parathyroid regeneration that could ultimately evolve into an improved clinical application. Copyright © 2017 John Wiley & Sons, Ltd.

Tonsil-derived mesenchymal stem cell-embedded in situ crosslinkable gelatin hydrogel therapy recovers postmenopausal osteoporosis through bone regeneration

“…As expected, subcutaneous injection of TMSC alone failed to reverse osteoporosis. Similar results were obtained for subcutaneous TMSC treatment of hypoparathyroidism, which showed therapeutic efficacy only with a scaffold use [ 15 , 17 ]. TMSC injected alone are likely to be diffused to surrounding area and lost to be nonfunctional, and GHH scaffold is essentially required for proper functioning of subcutaneously injected TMSC in this context.…”

“…They are highly proliferative (doubling time of 37.1 ± 3.4 h), more so than the bone marrow counterpart (doubling time of 58.2 ± 2.3 h) [ 7 ]. TMSC are suited to tissue engineering [ 8 ], and useful against various conditions, such as liver fibrosis [ 9 , 10 ], diabetes mellitus [ 11 ], allergic rhinitis [ 12 ], tenocyte regeneration [ 13 ], Charcot-Marie-Tooth disease [ 14 ] and hypoparathyroidism [ 15 – 17 ].…”

Application of Tonsil-Derived Mesenchymal Stem Cells in Tissue Regeneration: Concise Review

“…When the TMSC‐derived PTH‐releasing cells were fabricated with either Matrigel or GHH and were implanted at nape of parathyroidectomized (PTX) rats, vascularization around the implanted sites was observed. The PTX rats receiving these implants also showed higher levels of serum PTH, ionized Ca 2+ , and survival rates compared with those groups receiving no implants or implants containing nondifferentiated control TMSCs . Additionally, the subcutaneous injection of TMSCs differentiated into PTH‐releasing cells in the form of a scaffold‐free 3D spheroid showed similar results as it was observed from the studies with scaffolding materials .…”

Effect of Cross-Linking Density on the Structures and Properties of Carbodiimide-Treated Gelatin Matrices as Limbal Stem Cell Niches

“…In the field of tissue engineering, cross-linked gelatin matrices have been widely described for cultivation of mesenchymal stem cells from different sources [ 72 , 73 , 74 ]. To the best of our knowledge, the influence of cross-linking density of carbodiimide-treated gelatin matrices on the structures and properties of limbal stem cell niches has not been investigated yet.…”