Therapeutic effects and mechanism of human amnion-derived mesenchymal stem cells on hypercoagulability in a uremic calciphylaxis patient

Abstract

Calciphylaxis is a rare cutaneous vascular disease that manifests with intolerable pains, non-healing skin wounds, histologically characterized by calcification, fibrointimal hyperplasia, and microvessel thrombosis. Currently, there are no standardized guidelines for this disease. Recent studies have recognized a high prevalence of thrombophilias and hypercoagulable conditions in calciphylaxis patients. Here, we report a case of uremic calciphylaxis patient whom was refractory to conventional treatments and then received a salvage strategy with intravenous and local hAMSC application. In order to investigate the therapeutic mechanism of hAMSCs from the novel perspective of hypercoagulability, coagulation-related indicators, wound status, quality of life and skin biopsy were followed up. Polymerase chain reaction (PCR) was performed to determine the distribution of hAMSCs in multiple tissues including lung, kidney and muscle after infusion of hAMSCs for 24 h, 1 week and 1 month in mice aiming to investigate whether hAMSCs retain locally active roles after intravenous administration. Improvement of hypercoagulable condition involving correction of platelet, D-dimer and plasminogen levels, skin regeneration and pain alleviation were revealed after hAMSC administration over one-year period. Skin biopsy pathology suggested regenerative tissues after 1 month hAMSC application and full epidermal regeneration after 20 months hAMSC treatment. PCR analysis indicated that hAMSCs were homing in lung, kidney and muscle tissues of mice even until tail vein injection of hAMSCs for 1 month. We propose that hypercoagulability is a promising therapeutic target of calciphylaxis patients, which can be effectively improved by hAMSC treatment.

Keywords:

• Calciphylaxis
• chronic kidney disease
• hypercoagulability
• thrombophilias
• human amnion-derived mesenchymal stem cell

Acknowledgements

The authors thank the patient, her family and all medical staff who participated in the treatment and data collection. The study was supported by the International Society of Nephrology (ISN) Mentorship Program and the authors thank Professor Marcello Tonelli (University of Calgary, Canada) for his helpful comments on the draft of the manuscript. The patient and her family gave the consent for publication of the data obtained in the present study.

Ethical approval and consent to participate

The study was performed after an approval by the Ethics Committee of The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital (2018-QT-001). Healthy pregnant women in their 20s or 30s who provided written informed consent donated human amniotic membranes, which was approved by the Ethics Committee of Jiangsu Province Hospital (2012-SR-128).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This study was supported by the National Natural Science Foundation of China [81270408, 81570666, 81730041, and 81671447], the International Society of Nephrology (ISN) Clinical Research Program [18-01-0247], Construction Program of Jiangsu Provincial Clinical Research Center Support System [BL2014084], Jiangsu Province Key Medical Personnel Project [ZDRCA2016002], CKD Anemia Research Foundation from China International Medical Foundation [Z-2017-24-2037], Outstanding Young and Middle-Aged Talents Support Program of The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital), the National Key Research and Development Program of China [2017YFC1001303], the Program of Jiangsu Province Clinical Medical Center [YXZXB2016001, BL2012009], the State Key Laboratory of Reproductive Medicine Program [SKLRM-GC201803], and the Program of Jiangsu Commission of Health [H201605].