- Email: [email protected]
Adipose-derived stem cells: A novel source of parathyroid cells for treatment of hypoparathyroidism
Accepted Manuscript Adipose-derived stem cells: a novel source of parathyroid cells for treatment of hypoparathyroidism Yue Zhao, Bin Luo PII: DOI: Reference:
S0306-9877(16)30115-3 http://dx.doi.org/10.1016/j.mehy.2016.05.011 YMEHY 8274
To appear in:
Medical Hypotheses
Received Date: Accepted Date:
6 July 2015 12 May 2016
Please cite this article as: Y. Zhao, B. Luo, Adipose-derived stem cells: a novel source of parathyroid cells for treatment of hypoparathyroidism, Medical Hypotheses (2016), doi: http://dx.doi.org/10.1016/j.mehy.2016.05.011
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title page Title of the article: Adipose-derived stem cells: a novel source of parathyroid cells for treatment of hypoparathyroidism
First author: Yue Zhao (Zhao, Y), Master Degree Candidate Affiliation: Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
Corresponding Author: Bin Luo (Luo, B), M.D. Affiliation: Department of General Surgery, Beijing Tsinghua Changgung Hospital, Tsinghua University Medical Center, Beijing, China Telephone: + (86)13621105367 Fax number: + (86)01056119112 Email address: [email protected]
The work should be attributed to: Department of General Surgery, Xuanwu Hospital, Capital Medical University Address: No.45 Changchun District, Xuanwu District, Beijing And Department of General Surgery, Beijing Tsinghua Changgung Hospital, Tsinghua University Medical Center, Beijing, China Address: No.168 Litang Road, Changping District, Beijing, 102218
Funding: Beijing Municipal Project Financing for High-level Technical Talents in Health System (Dr. Bin Luo) Grant No. 20132032
Adipose-derived stem cells: a novel source of parathyroid cells for treatment of hypoparathyroidism Abstract Hypoparathyroidism is characterized by decreased function of the parathyroid glands with underproduction of parathyroid hormone (PTH), which can lead to low levels of calcium in the blood, often causing cramping and twitching of muscles or tetany, and several other symptoms. Severe hypocalcemia is a life-threatening condition. At present, both medical and surgical treatments are offered to improve the blood calcium, but they are not a cure. Adipose-derived stem cells (ADSCs), derived from the adipose tissue, are confirmed to be multipotent with adipogenic, chondrogenic, neurogenic, myogenic and osteogenic capabilities. Our hypothesis is that human ADSCs in culture can be differentiated into parathyroid cells, and used to reconstitute function. Hypoparathyroidism Hypoparathyroidism is a rare endocrine deficiency disease characterized by low serum calcium levels, elevated serum phosphorus levels, and absent or inappropriately low levels of PTH in the circulation [1]. The causes of hypoparathyroidism are diverse, but injury to or removal of the parathyroid glands during thyroid surgery is the most common etiology of acute or chronic hypoparathyroidism [2]. Removal of the parathyroid glands or disruption of the blood supply to the glands can lead to transient, and rarely permanent hypoparathyroidism. The clinical features of hypoparathyroidism are mainly caused by hypocalcemia; patients
can
experience acroanesthesia,
tetany, fatigue, headaches,
bone
pain and several other symptoms [3, 4]. Severe hypocalcemia is a life-threatening condition.
Treatment of hypoparathyroidism At present, the main treatments available for patients with acute or chronic hypoparathyroidism are calcium salts, vitamin D or its analogs, and drugs that increase renal tubular reabsorption of calcium (i.e., thiazides) [2]. Conventional treatment always faces the challenge to maintain normocalcemia, while hypercalciuria and ectopic calcification have also been found with these supplements. So it is necessary for patients to closely monitor their serum calcium levels, and also be aware of potential interactions with food and other medications that may cause side effects. Recently, recombinant parathyroid hormone (rPTH) was shown to be an alternative to conventional treatment in numerous studies. As compared to conventional treatment, rPTH increases the renal tubular reabsorption of calcium and may lower urinary calcium, thereby protecting against renal calcifications [5]. In June 2015, the FDA approved a subcutaneously injected formulation of human rPTH (Natpara – NPS) as an adjunct to calcium and vitamin D to control hypocalcemia in adults
with
hypoparathyroidism. Natpara is
an
84-amino
acid
single-chain
polypeptide identical to native PTH. It is the first PTH formulation to be approved for this indication [6]. However, the long-term efficacy of rPTH therapy is uncertain and the exorbitant price limits its clinical application. Prospective, large, long-term trials are necessary to evaluate the long-term efficacy and adverse profile of rPTH [7]. Transplantation of parathyroid tissue is appealing but rarely possible. Routine parathyroid
autotransplantation
during
thyroidectomy
virtually
eliminates
postoperative hypoparathyroidism [8]. However, intraoperative identification of damaged parathyroid glands with decreased vascularity may be difficult [9]. A parathyroid allograft would require immunosuppression, which would be more
dangerous than the disease it was meant to treat. Some clinical cases have confirmed that combination of tissue-culture passage and microencapsulation could make parathyroid allotransplantation a practical option for successful treatment of permanent hypoparathyroidism [10-13]. But several factors need to be considered to optimize this therapy, namely material porosity, biocompatibility, and long-term resistance. Adipose-derived stem cells A multipotent stem cell is defined as a special cell that has the unique capacity to self-renew for indefinite periods. Therefore, stem cells can be extensively expanded ex vivo. The potential use of stem cell-based therapies for the repair and regeneration of various tissues and organs offers a paradigm shift that may provide alternative therapeutic solutions for several diseases. Stem cell candidates include embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and postnatal adult stem cells [14]. In 1981, the isolation of mouse ESCs became possible with the discovery of techniques that allowed the cells to be grown in the laboratory [15]. The exploration of mouse ESCs stimulated the interest in the isolation of analogous cells of human origin and human ESCs were established [16]. However, the safety and efficacy as well as ethical, legal, and political concerns regarding the use of human ESCs remain controversial. iPSCs are derived from differentiated cells such as bone marrow, skin, blood vessels, muscle, brain, etc. Although the stem cells population derived from these sources are valuable, problems such as pain, morbidity and low cell number upon harvest limit their practical use [18]. In contrast, postnatal adult stem cells are, by nature, immunocompatible, and there are no ethical concerns related to their use. Herein, we discuss about multipotent stem cells derived from human adipose tissue, which named adipose-derived stem cells (ADSCs). ADSCs are able to
undergo
adipogenic,
chondrogenic,
neurogenic,
myogenic
and
osteogenic
differentiation in vitro [17-21]. Moreover, adipose tissue is ubiquitous and can be harvested by liposuction with minimal risk, and the techniques of isolation, expansion and differentiation of ADSCs are relatively mature [22]. ADSCs remain viable under adverse conditions of low glucose, glutamine, and oxygen concentrations [23]. Therefore, the use of ADSCs as research tools and cellular therapeutics is feasible and was shown to be safe and efficacious in both animal models and clinical studies [2428]. Though adipose tissue has not yet been completely understood, the advantages mentioned above make it a better candidate for cell therapy, which will be beneficial to
the
patients
in
the
future.
Theory of the hypothesis Replacement of a diseased organ with an autologously derived cell is an ideal therapy for some medical problems. Hypoparathyroidism can seriously affect the psychological and mental quality of life of the patient. The nature and simplicity of the parathyroid glands makes hypoparathyroidism an ideal candidate for treatment by cellular replacement [29]. The differentiation potential of ADSCs facilitates autologous cellular replacement therapy for hypoparathyroidism. We hypothesize that ADSCs, derived from human adipose tissue, can be differentiated into parathyroid cells for treatment of hypoparathyroidism. Calcium-sensing receptor (CaSR), GCM2, and PTH expression, and PTH protein secretion will be used as markers to confirm the differentiated cells. Afterwards, we will inject the cells under the fascia of the non-dominant forearm. The induced differentiation of ADSCs and the response of differentiated cells to blood calcium concentration will play key roles in the whole process.
Evaluation of the hypothesis Our hypothesis is supported by several facts: (1) Woods et al. have reported that both human ESCs and thymus cells could be successfully differentiated to parathyroid-like cells. The cells expressed CaSR, GCM2, PTH RNA, and also secreted PTH [29, 30]. Given the multipotency of stem cells, it is similarly possible for ADSCs. We are proficient in the techniques to test those markers. (2) Adipose tissue can be easily obtained by liposuction from the patients, thereby lowering the possibility of immunological rejection and ethical problems after transplantation. (3) The transplantation site is chosen because of the ease of monitoring of transplant function based on the differences in the PTH gradient across both arms and a welldeveloped vascular network that ensures proper oxygen and nutrient supply to the transplanted cells [31]. Additional studies are needed to confirm the hypothesis. We plan to assess whether the cells can compensate for PTH deficiency in an animal model. The symptom of low calcium, levels of blood calcium and PTH will be used to measure the results. Conflict of interest None Funding: Beijing Municipal Project Financing for High-level Technical Talents in Health System, Grant No. 20132032.
References: [1]Bilezikian JP, Khan A, Potts JT, et al. Hypoparathyroidism in the adult: Epidemiology, diagnosis, pathophysiology, target-organ involvement, treatment, and challenges for future research. J Bone Miner Res 2011; 26(10): 2317-2337. [2]Marx SJ. Hyperparathyroid and hypoparathyroid disorders. N Engl J Med 2000; 343(25): 1863-1875. [3]Murphy E, Williams GR. Hypocalcaemia. Medicine 2009; 37 (9): 465-468. [4]Dolores Shoback MD. Hypoparathyroidism. N Engl J Med 2008; 359(4): 391-403. [5]Rejnmark L, Underbjerg L, Sikjaer T. Therapy of Hypoparathyroidism by Replacement with Parathyroid Hormone. Scientifica 2014; 2014: 1-8. [6]Recombinant human parathyroid hormone (Natpara). Med Lett Drugs Ther 2015; 57(1470): 87-88. [7]Ramakrishnan Y, Cocks HC. Impact of recombinant PTH on management of hypoparathyroidism: a systematic review. Eur Arch Otorhinolaryngol 2015: 1-9. [8]Olson JJ, DeBenedetti MK, Baumann DS, et al. Parathyroid autotransplantation during thyroidectomy. Results of long-term follow-up. Ann Surg 1996; 223(5): 472478, 478-480. [9]LO
C.
PARATHYROID
AUTOTRANSPLANTATION
DURING
THYROIDECTOMY. ANZ J. Surg 2002; 12(72): 902-907. [10]Hasse C, Schlosser A, Zimmermann U, Rothmund M, et al. Parathyroid allotransplantation without immunosuppression. The Lancet 1997; 350(9087): 12961297. [11]Cabané P, Gac P, Amat J, et al. Allotransplant of Microencapsulated Parathyroid Tissue in Severe Postsurgical Hypoparathyroidism: A Case Report. TRANSPL P 2009; 41(9): 3879-3883. [12]Moskalenko V, Ulrichs K, Kerscher A, et al. Preoperative evaluation of microencapsulated human parathyroid tissue aids selection of the optimal bioartificial graft for human parathyroid allotransplantation. Transpl int 2007; 20(8): 688-696. [13]Tsuji K, Fuchinoue S, Kai K, et al. Culture of human parathyroid cells for transplantation, Transplant Proc 1999; 31 (7): 2697. [14]Mizuno H, Tobita M, Uysal AC. Concise review: Adipose-derived stem cells as a novel tool for future regenerative medicine. Stem Cells 2012; 30(5): 804-810. [15]Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature 1981; 292(5819): 154-156.
[16]Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embryonic Stem Cell Lines Derived from Human Blastocysts. Science 1998; 282(5391): 1145-1147. [17]Zuk PA, Zhu M, Mizuno H, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 2001; 7(2): 211-228. [18]Zuk PA, Zhu M, Ashjian P, et al. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 2002; 13(12): 4279-4295. [19]Rodriguez AM, Elabd C, Amri EZ, et al. The human adipose tissue is a source of multipotent stem cells. Biochimie 2005; 87(1): 125-128. [20]Fraser JK, Wulur I, Alfonso Z, et al. Fat tissue: an underappreciated source of stem cells for biotechnology. Trends in Biotechnology 2006; 24(4): 150-154. [21]Rodriguez AM, Elabd C, Delteil F, et al. Adipocyte differentiation of multipotent cells established from human adipose tissue. Biochem Biophys Res Commun 2004; 315(2): 255-263. [22]BUNNELL B, FLAAT M, GAGLIARDI C, et al. Adipose-derived stem cells: Isolation, expansion and differentiation. Methods 2008; 45(2): 115-120. [23]Mischen BT, Follmar KE, Moyer KE, et al. Metabolic and Functional Characterization of Human Adipose-Derived Stem Cells in Tissue Engineering. Plast Reconstr Surg 2008; 122(3): 725-738. [24]Yuan J, Li W, Huang J, et al. Transplantation of human adipose stem cell-derived hepatocyte-like cells with restricted localization to liver using acellular amniotic membrane. Stem Cell Res Ther 2015; 6(1):217. [25]Díaz-Agero Álvarez PJ, Bellido-Reyes YA, Sánchez-Girón JG, et al. Novel bronchoscopic treatment for bronchopleural fistula using adipose-derived stromal cells. Cytotherapy 2016; 18(1): 36-40. [26]Lim JS, Yoo G. Effects of Adipose-derived Stromal Cells and of their Extract on Wound Healing in a Mouse Model. J Korean Med Sci 2010; 25(5): 746-751. [27]Garimella MG, Kour S, Piprode V, et al. Adipose-Derived Mesenchymal Stem Cells Prevent Systemic Bone Loss in Collagen-Induced Arthritis. J Immunol 2015; 195(11): 5136-5148. [28]Borowski DW, Gill TS, Agarwal AK, et al. Adipose Tissue-Derived Regenerative Cell-Enhanced Lipofilling for Treatment of Cryptoglandular Fistulae-in-Ano: The ALFA Technique. Surg Innov 2015; 22 (6): 593-600. [29]Woods Ignatoski KM, Bingham EL, Frome LK, et al. Differentiation of precursors into parathyroid-like cells for treatment of hypoparathyroidism. Surgery
2010; 148(6): 1186-1190. [30]Woods Ignatoski KM, Bingham EL, Frome LK, et al. Directed trans differentiation of thymus cells into parathyroid-Like Cells Without Genetic Manipulation. Tissue Eng Part C Methods 2011; 17(11): 1051-1059. [31]Nawrot I, Sawicki A, Szmidt J, et al. Allotransplantation of Cultured Parathyroid Progenitor Cells Without Immunosuppression: Clinical Results. Transplantation 2007; 83(6): 734-740.
S0306-9877(16)30115-3 http://dx.doi.org/10.1016/j.mehy.2016.05.011 YMEHY 8274
To appear in:
Medical Hypotheses
Received Date: Accepted Date:
6 July 2015 12 May 2016
Please cite this article as: Y. Zhao, B. Luo, Adipose-derived stem cells: a novel source of parathyroid cells for treatment of hypoparathyroidism, Medical Hypotheses (2016), doi: http://dx.doi.org/10.1016/j.mehy.2016.05.011
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title page Title of the article: Adipose-derived stem cells: a novel source of parathyroid cells for treatment of hypoparathyroidism
First author: Yue Zhao (Zhao, Y), Master Degree Candidate Affiliation: Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
Corresponding Author: Bin Luo (Luo, B), M.D. Affiliation: Department of General Surgery, Beijing Tsinghua Changgung Hospital, Tsinghua University Medical Center, Beijing, China Telephone: + (86)13621105367 Fax number: + (86)01056119112 Email address: [email protected]
The work should be attributed to: Department of General Surgery, Xuanwu Hospital, Capital Medical University Address: No.45 Changchun District, Xuanwu District, Beijing And Department of General Surgery, Beijing Tsinghua Changgung Hospital, Tsinghua University Medical Center, Beijing, China Address: No.168 Litang Road, Changping District, Beijing, 102218
Funding: Beijing Municipal Project Financing for High-level Technical Talents in Health System (Dr. Bin Luo) Grant No. 20132032
Adipose-derived stem cells: a novel source of parathyroid cells for treatment of hypoparathyroidism Abstract Hypoparathyroidism is characterized by decreased function of the parathyroid glands with underproduction of parathyroid hormone (PTH), which can lead to low levels of calcium in the blood, often causing cramping and twitching of muscles or tetany, and several other symptoms. Severe hypocalcemia is a life-threatening condition. At present, both medical and surgical treatments are offered to improve the blood calcium, but they are not a cure. Adipose-derived stem cells (ADSCs), derived from the adipose tissue, are confirmed to be multipotent with adipogenic, chondrogenic, neurogenic, myogenic and osteogenic capabilities. Our hypothesis is that human ADSCs in culture can be differentiated into parathyroid cells, and used to reconstitute function. Hypoparathyroidism Hypoparathyroidism is a rare endocrine deficiency disease characterized by low serum calcium levels, elevated serum phosphorus levels, and absent or inappropriately low levels of PTH in the circulation [1]. The causes of hypoparathyroidism are diverse, but injury to or removal of the parathyroid glands during thyroid surgery is the most common etiology of acute or chronic hypoparathyroidism [2]. Removal of the parathyroid glands or disruption of the blood supply to the glands can lead to transient, and rarely permanent hypoparathyroidism. The clinical features of hypoparathyroidism are mainly caused by hypocalcemia; patients
can
experience acroanesthesia,
tetany, fatigue, headaches,
bone
pain and several other symptoms [3, 4]. Severe hypocalcemia is a life-threatening condition.
Treatment of hypoparathyroidism At present, the main treatments available for patients with acute or chronic hypoparathyroidism are calcium salts, vitamin D or its analogs, and drugs that increase renal tubular reabsorption of calcium (i.e., thiazides) [2]. Conventional treatment always faces the challenge to maintain normocalcemia, while hypercalciuria and ectopic calcification have also been found with these supplements. So it is necessary for patients to closely monitor their serum calcium levels, and also be aware of potential interactions with food and other medications that may cause side effects. Recently, recombinant parathyroid hormone (rPTH) was shown to be an alternative to conventional treatment in numerous studies. As compared to conventional treatment, rPTH increases the renal tubular reabsorption of calcium and may lower urinary calcium, thereby protecting against renal calcifications [5]. In June 2015, the FDA approved a subcutaneously injected formulation of human rPTH (Natpara – NPS) as an adjunct to calcium and vitamin D to control hypocalcemia in adults
with
hypoparathyroidism. Natpara is
an
84-amino
acid
single-chain
polypeptide identical to native PTH. It is the first PTH formulation to be approved for this indication [6]. However, the long-term efficacy of rPTH therapy is uncertain and the exorbitant price limits its clinical application. Prospective, large, long-term trials are necessary to evaluate the long-term efficacy and adverse profile of rPTH [7]. Transplantation of parathyroid tissue is appealing but rarely possible. Routine parathyroid
autotransplantation
during
thyroidectomy
virtually
eliminates
postoperative hypoparathyroidism [8]. However, intraoperative identification of damaged parathyroid glands with decreased vascularity may be difficult [9]. A parathyroid allograft would require immunosuppression, which would be more
dangerous than the disease it was meant to treat. Some clinical cases have confirmed that combination of tissue-culture passage and microencapsulation could make parathyroid allotransplantation a practical option for successful treatment of permanent hypoparathyroidism [10-13]. But several factors need to be considered to optimize this therapy, namely material porosity, biocompatibility, and long-term resistance. Adipose-derived stem cells A multipotent stem cell is defined as a special cell that has the unique capacity to self-renew for indefinite periods. Therefore, stem cells can be extensively expanded ex vivo. The potential use of stem cell-based therapies for the repair and regeneration of various tissues and organs offers a paradigm shift that may provide alternative therapeutic solutions for several diseases. Stem cell candidates include embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and postnatal adult stem cells [14]. In 1981, the isolation of mouse ESCs became possible with the discovery of techniques that allowed the cells to be grown in the laboratory [15]. The exploration of mouse ESCs stimulated the interest in the isolation of analogous cells of human origin and human ESCs were established [16]. However, the safety and efficacy as well as ethical, legal, and political concerns regarding the use of human ESCs remain controversial. iPSCs are derived from differentiated cells such as bone marrow, skin, blood vessels, muscle, brain, etc. Although the stem cells population derived from these sources are valuable, problems such as pain, morbidity and low cell number upon harvest limit their practical use [18]. In contrast, postnatal adult stem cells are, by nature, immunocompatible, and there are no ethical concerns related to their use. Herein, we discuss about multipotent stem cells derived from human adipose tissue, which named adipose-derived stem cells (ADSCs). ADSCs are able to
undergo
adipogenic,
chondrogenic,
neurogenic,
myogenic
and
osteogenic
differentiation in vitro [17-21]. Moreover, adipose tissue is ubiquitous and can be harvested by liposuction with minimal risk, and the techniques of isolation, expansion and differentiation of ADSCs are relatively mature [22]. ADSCs remain viable under adverse conditions of low glucose, glutamine, and oxygen concentrations [23]. Therefore, the use of ADSCs as research tools and cellular therapeutics is feasible and was shown to be safe and efficacious in both animal models and clinical studies [2428]. Though adipose tissue has not yet been completely understood, the advantages mentioned above make it a better candidate for cell therapy, which will be beneficial to
the
patients
in
the
future.
Theory of the hypothesis Replacement of a diseased organ with an autologously derived cell is an ideal therapy for some medical problems. Hypoparathyroidism can seriously affect the psychological and mental quality of life of the patient. The nature and simplicity of the parathyroid glands makes hypoparathyroidism an ideal candidate for treatment by cellular replacement [29]. The differentiation potential of ADSCs facilitates autologous cellular replacement therapy for hypoparathyroidism. We hypothesize that ADSCs, derived from human adipose tissue, can be differentiated into parathyroid cells for treatment of hypoparathyroidism. Calcium-sensing receptor (CaSR), GCM2, and PTH expression, and PTH protein secretion will be used as markers to confirm the differentiated cells. Afterwards, we will inject the cells under the fascia of the non-dominant forearm. The induced differentiation of ADSCs and the response of differentiated cells to blood calcium concentration will play key roles in the whole process.
Evaluation of the hypothesis Our hypothesis is supported by several facts: (1) Woods et al. have reported that both human ESCs and thymus cells could be successfully differentiated to parathyroid-like cells. The cells expressed CaSR, GCM2, PTH RNA, and also secreted PTH [29, 30]. Given the multipotency of stem cells, it is similarly possible for ADSCs. We are proficient in the techniques to test those markers. (2) Adipose tissue can be easily obtained by liposuction from the patients, thereby lowering the possibility of immunological rejection and ethical problems after transplantation. (3) The transplantation site is chosen because of the ease of monitoring of transplant function based on the differences in the PTH gradient across both arms and a welldeveloped vascular network that ensures proper oxygen and nutrient supply to the transplanted cells [31]. Additional studies are needed to confirm the hypothesis. We plan to assess whether the cells can compensate for PTH deficiency in an animal model. The symptom of low calcium, levels of blood calcium and PTH will be used to measure the results. Conflict of interest None Funding: Beijing Municipal Project Financing for High-level Technical Talents in Health System, Grant No. 20132032.
References: [1]Bilezikian JP, Khan A, Potts JT, et al. Hypoparathyroidism in the adult: Epidemiology, diagnosis, pathophysiology, target-organ involvement, treatment, and challenges for future research. J Bone Miner Res 2011; 26(10): 2317-2337. [2]Marx SJ. Hyperparathyroid and hypoparathyroid disorders. N Engl J Med 2000; 343(25): 1863-1875. [3]Murphy E, Williams GR. Hypocalcaemia. Medicine 2009; 37 (9): 465-468. [4]Dolores Shoback MD. Hypoparathyroidism. N Engl J Med 2008; 359(4): 391-403. [5]Rejnmark L, Underbjerg L, Sikjaer T. Therapy of Hypoparathyroidism by Replacement with Parathyroid Hormone. Scientifica 2014; 2014: 1-8. [6]Recombinant human parathyroid hormone (Natpara). Med Lett Drugs Ther 2015; 57(1470): 87-88. [7]Ramakrishnan Y, Cocks HC. Impact of recombinant PTH on management of hypoparathyroidism: a systematic review. Eur Arch Otorhinolaryngol 2015: 1-9. [8]Olson JJ, DeBenedetti MK, Baumann DS, et al. Parathyroid autotransplantation during thyroidectomy. Results of long-term follow-up. Ann Surg 1996; 223(5): 472478, 478-480. [9]LO
C.
PARATHYROID
AUTOTRANSPLANTATION
DURING
THYROIDECTOMY. ANZ J. Surg 2002; 12(72): 902-907. [10]Hasse C, Schlosser A, Zimmermann U, Rothmund M, et al. Parathyroid allotransplantation without immunosuppression. The Lancet 1997; 350(9087): 12961297. [11]Cabané P, Gac P, Amat J, et al. Allotransplant of Microencapsulated Parathyroid Tissue in Severe Postsurgical Hypoparathyroidism: A Case Report. TRANSPL P 2009; 41(9): 3879-3883. [12]Moskalenko V, Ulrichs K, Kerscher A, et al. Preoperative evaluation of microencapsulated human parathyroid tissue aids selection of the optimal bioartificial graft for human parathyroid allotransplantation. Transpl int 2007; 20(8): 688-696. [13]Tsuji K, Fuchinoue S, Kai K, et al. Culture of human parathyroid cells for transplantation, Transplant Proc 1999; 31 (7): 2697. [14]Mizuno H, Tobita M, Uysal AC. Concise review: Adipose-derived stem cells as a novel tool for future regenerative medicine. Stem Cells 2012; 30(5): 804-810. [15]Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature 1981; 292(5819): 154-156.
[16]Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embryonic Stem Cell Lines Derived from Human Blastocysts. Science 1998; 282(5391): 1145-1147. [17]Zuk PA, Zhu M, Mizuno H, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 2001; 7(2): 211-228. [18]Zuk PA, Zhu M, Ashjian P, et al. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 2002; 13(12): 4279-4295. [19]Rodriguez AM, Elabd C, Amri EZ, et al. The human adipose tissue is a source of multipotent stem cells. Biochimie 2005; 87(1): 125-128. [20]Fraser JK, Wulur I, Alfonso Z, et al. Fat tissue: an underappreciated source of stem cells for biotechnology. Trends in Biotechnology 2006; 24(4): 150-154. [21]Rodriguez AM, Elabd C, Delteil F, et al. Adipocyte differentiation of multipotent cells established from human adipose tissue. Biochem Biophys Res Commun 2004; 315(2): 255-263. [22]BUNNELL B, FLAAT M, GAGLIARDI C, et al. Adipose-derived stem cells: Isolation, expansion and differentiation. Methods 2008; 45(2): 115-120. [23]Mischen BT, Follmar KE, Moyer KE, et al. Metabolic and Functional Characterization of Human Adipose-Derived Stem Cells in Tissue Engineering. Plast Reconstr Surg 2008; 122(3): 725-738. [24]Yuan J, Li W, Huang J, et al. Transplantation of human adipose stem cell-derived hepatocyte-like cells with restricted localization to liver using acellular amniotic membrane. Stem Cell Res Ther 2015; 6(1):217. [25]Díaz-Agero Álvarez PJ, Bellido-Reyes YA, Sánchez-Girón JG, et al. Novel bronchoscopic treatment for bronchopleural fistula using adipose-derived stromal cells. Cytotherapy 2016; 18(1): 36-40. [26]Lim JS, Yoo G. Effects of Adipose-derived Stromal Cells and of their Extract on Wound Healing in a Mouse Model. J Korean Med Sci 2010; 25(5): 746-751. [27]Garimella MG, Kour S, Piprode V, et al. Adipose-Derived Mesenchymal Stem Cells Prevent Systemic Bone Loss in Collagen-Induced Arthritis. J Immunol 2015; 195(11): 5136-5148. [28]Borowski DW, Gill TS, Agarwal AK, et al. Adipose Tissue-Derived Regenerative Cell-Enhanced Lipofilling for Treatment of Cryptoglandular Fistulae-in-Ano: The ALFA Technique. Surg Innov 2015; 22 (6): 593-600. [29]Woods Ignatoski KM, Bingham EL, Frome LK, et al. Differentiation of precursors into parathyroid-like cells for treatment of hypoparathyroidism. Surgery
2010; 148(6): 1186-1190. [30]Woods Ignatoski KM, Bingham EL, Frome LK, et al. Directed trans differentiation of thymus cells into parathyroid-Like Cells Without Genetic Manipulation. Tissue Eng Part C Methods 2011; 17(11): 1051-1059. [31]Nawrot I, Sawicki A, Szmidt J, et al. Allotransplantation of Cultured Parathyroid Progenitor Cells Without Immunosuppression: Clinical Results. Transplantation 2007; 83(6): 734-740.