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本発明は、例えば、以下の項目を提供する。
(項目1)
組織の再生を促進する方法であって、前記組織を1つ以上の脂肪酸酸化活性化因子(「FAO活性化因子」)と接触させることを含む、前記方法。
(項目2)
組織の成長を促進する方法であって、前記組織を1つ以上のFAO活性化因子と接触させることを含む、前記方法。
(項目3)
組織内の組織形成細胞の分化及び/または成熟を誘導する方法であって、前記組織を1つ以上のFAO活性化因子と接触させることを含む、前記方法。
(項目4)
組織内の幹細胞または組織形成細胞の増殖を誘導する方法であって、前記組織を1つ以上のFAO活性化因子と接触させることを含む、前記方法。
(項目5)
前記組織が、高齢個体由来である、項目1~4のいずれか1項に記載の方法。
(項目6)
前記組織が、約72時間以下、約48時間以下、または約24時間以下、前記1つ以上のFAO活性化因子と接触する、項目1~5のいずれか1項に記載の方法。
(項目7)
前記接触させることが、インビトロまたはエクスビボである、項目1~6のいずれか1項に記載の方法。
(項目8)
前記接触させることが、インビボである、項目1~6のいずれか1項に記載の方法。
(項目9)
個体における組織に関連する疾患または状態を治療する方法であって、組織形成細胞を含む有効量の薬学的組成物を前記個体の前記組織に投与することを含み、前記組織形成細胞が、前記薬学的組成物の前記投与の前に1つ以上のFAO活性化因子と接触する、前記方法。
(項目10)
前記方法が、前記薬学的組成物の前記投与の前に、前記組織形成細胞を前記1つ以上のFAO活性化因子と接触させることを含む、項目9に記載の方法。
(項目11)
前記組織形成細胞が、約72時間以下、約48時間以下、または約24時間以下、前記1つ以上のFAO活性化因子と接触する、項目9または10に記載の方法。
(項目12)
前記組織形成細胞が、自己性である、項目9~11のいずれか1項に記載の方法。
(項目13)
前記組織形成細胞が、同種異系である、項目9~11のいずれか1項に記載の方法。
(項目14)
個体における組織に関連する疾患または状態を治療する方法であって、1つ以上のFAO活性化因子を含む有効量の薬学的組成物を前記個体に投与することを含む、前記方法。
(項目15)
前記疾患または状態が、組織傷害である、項目9~14のいずれか1項に記載の方法。
(項目16)
前記疾患または状態が、組織変性または組織線維症である、項目9~15のいずれか1項に記載の方法。
(項目17)
前記疾患または状態が、老化である、項目9~17のいずれか1項に記載の方法。
(項目18)
前記疾患または状態が、サルコペニア、悪液質、廃用性萎縮、炎症性筋疾患、筋ジストロフィー、心筋症、皮膚しわ、難治性皮膚潰瘍、皮膚創傷、水疱症、脱毛症、ケロイド、皮膚炎、黄斑変性症、大腸炎、脂肪肝、脂肪性肝炎、肝線維症、肝硬変、膵炎、2型糖尿病(T2D)、脂肪異栄養症、慢性閉塞性肺疾患(COPD)、肺線維症、急性呼吸窮迫症候群(ARDS)、関節リウマチ、変形性関節症、骨粗しょう症、神経変性疾患、脳梗塞、心筋梗塞、肺梗塞、骨折、胃潰瘍、腸炎、慢性腎臓病、腎線維症、ならびに組織/臓器/身体部分の構造及び機能の喪失もしくは萎縮を引き起こす他の遺伝的に決定された、環境的に決定された、または特発性の疾患過程からなる群から選択される、項目9~18のいずれか1項に記載の方法。
(項目19)
運動及び/または栄養の1つ以上の利点を個体の組織に提供する方法であって、1つ以上のFAO活性化因子を含む有効量の薬学的組成物を前記個体に投与することを含む、前記方法。
(項目20)
前記組織が、傷害組織である、項目1~19のいずれか1項に記載の方法。
(項目21)
前記薬学的組成物が、前記組織傷害後、約72時間以内、約48時間以内、または約24時間以内に、前記個体に投与される、項目20に記載の方法。
(項目22)
前記組織が、損傷を受けていない、項目1~19のいずれか1項に記載の方法。
(項目23)
前記組織が、筋肉組織、肝臓組織、心臓組織、皮膚組織、及び毛包からなる群から選択される、項目1~22のいずれか1項に記載の方法。
(項目24)
前記組織が、筋肉組織である、項目23に記載の方法。
(項目25)
前記組織形成細胞が、筋原性細胞である、項目24に記載の方法。
(項目26)
前記筋原性細胞が、筋芽細胞及び/または筋細胞である、項目25に記載の方法。
(項目27)
前記薬学的組成物が、24時間毎、48時間毎、または72時間毎に1回、前記個体に投与される、項目14~26のいずれか1項に記載の方法。
(項目28)
前記薬学的組成物が、前記個体の前記組織に投与される、項目14~27のいずれか1項に記載の方法。
(項目29)
前記薬学的組成物が、筋肉内投与される、項目28に記載の方法。
(項目30)
前記薬学的組成物が、皮下投与される、項目28に記載の方法。
(項目31)
前記薬学的組成物が、前記個体に全身投与される、項目14~27のいずれか1項に記載の方法。
(項目32)
前記個体が、高齢個体である、項目9~31のいずれか1項に記載の方法。
(項目33)
前記1つ以上のFAO活性化因子が、
(1)筋原性細胞におけるミトコンドリアFAOを増加させる、
(2)筋原性細胞におけるミトコンドリア酸素消費量を増加させる、
(3)筋原性細胞におけるミトコンドリア生物発生に影響を及ぼさない、
(4)筋原性細胞の膜電位に影響を及ぼさない、及び/または
(5)筋原性細胞におけるPAX7、MyoD、Ki67、MyoG、Myh3、PPARγ、PPARα、及び/またはH3K9acのレベル(複数可)を増加させる、項目1~32のいずれか1項に記載の方法。
(項目34)
前記1つ以上のFAO活性化因子が、FAO経路または脂質代謝経路における遺伝子の活性化因子を含む、項目1~33のいずれか1項に記載の方法。
(項目35)
前記1つ以上のFAO活性化因子が、脂質代謝の転写調節因子、脂肪酸輸送体、リパーゼ、カルニチンパルミトイル-トランスフェラーゼ、カルニチンアセチラーゼ、アシル-CoAデヒドロゲナーゼ、ヒドロキシアシル-CoAデヒドロゲナーゼ、及びミトコンドリア電子伝達フラボタンパク質からなる群から選択される遺伝子の活性化因子を含む、項目1~34のいずれか1項に記載の方法。
(項目36)
前記1つ以上のFAO活性化因子が、PPARα、PPARδ、PPARγ、RXRB、RXRG、NCOA1、NCOA2、FABP3、FABP4、CD36、SCARB1、FATP1、FATP2、FATP3、FATP4、FATP5、FATP6、LPL、CPT1A、CPT1B、CPT1C、CPT2、CRAT、ACAD1、ACAD2、ACAD3、ACAD4、ACAD5、ACAD6、ACAD7、ACAD8、ACAD9、ACAD10、ACAD11、MCAD、LCAD、VLCAD、HADHA、HADHB、ETFA、及びETFBからなる群から選択される遺伝子の活性化因子を含む、項目35に記載の方法。
(項目37)
前記1つ以上のFAO活性化因子が、1つ以上のPPARγ活性化因子を含む、項目1~36のいずれか1項に記載の方法。
(項目38)
組織形成細胞内のFAOを増加させる方法であって、前記組織形成細胞を、約72時間以下、1つ以上のPPARγ活性化因子と接触させることを含む、前記方法。
(項目39)
組織形成細胞内のPPARγを活性化させる方法であって、前記組織形成細胞を、プロスタグランジンI2(PGI2)、プロスタグランジンD2(PGD2)、それらの類似体、ならびにそれらの塩、溶媒和物、互変異性体及び立体異性体からなる群から選択されるプロスタグランジンと接触させることを含む、前記方法。
(項目40)
前記組織形成細胞が、筋原性細胞である、項目38または39のいずれか1項に記載の方法。
(項目41)
前記筋原性細胞が、筋芽細胞または筋細胞である、項目40に記載の方法。
(項目42)
前記1つ以上のPPARγ活性化因子が、PPARγアゴニストを含む、項目37~38及び40~41のいずれか1項に記載の方法。
(項目43)
前記PPARγアゴニストが、チアゾリジンジオンもしくはその誘導体、またはその塩、溶媒和物、互変異性体もしくは立体異性体である、項目42に記載の方法。
(項目44)
前記PPARγアゴニストが、ロシグリタゾン、またはその塩、溶媒和物、互変異性体もしくは立体異性体である、項目43に記載の方法。
(項目45)
前記1つ以上のPPARγ活性化因子が、PGI2、PGD2、それらの類似体、ならびにそれらの塩、溶媒和物、互変異性体及び立体異性体からなる群から選択されるプロスタグランジンを含む、項目37~38及び40~44のいずれか1項に記載の方法。
(項目46)
前記プロスタグランジンが、PGI2、またはその塩、溶媒和物、互変異性体もしくは立体異性体である、項目39~41及び45のいずれか1項に記載の方法。
(項目47)
前記1つ以上のPPARγ活性化因子が、ロシグリタゾン及びPGI2である、項目46に記載の方法。
(項目48)
前記プロスタグランジンが、トレプロスチニル、またはその塩、溶媒和物、互変異性体もしくは立体異性体である、項目39~41及び45のいずれか1項に記載の方法。
(項目49)
前記1つ以上のPPARγ活性化因子が、ロシグリタゾン及びトレプロスチニルである、項目48に記載の方法。
(項目50)
組織形成細胞を含む薬学的組成物であって、前記組織形成細胞が、約72時間以下、1つ以上のFAO活性化因子と接触する、前記薬学的組成物。
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The present invention provides, for example, the following items.
(Item 1)
A method of promoting tissue regeneration, the method comprising contacting the tissue with one or more fatty acid oxidation activators (“FAO activators”).
(Item 2)
A method of promoting tissue growth, the method comprising contacting the tissue with one or more FAO activators.
(Item 3)
A method of inducing differentiation and/or maturation of tissue-forming cells in a tissue, said method comprising contacting said tissue with one or more FAO activators.
(Item 4)
A method of inducing proliferation of stem cells or tissue-forming cells in a tissue, the method comprising contacting the tissue with one or more FAO activators.
(Item 5)
The method according to any one of items 1 to 4, wherein the tissue is derived from an elderly individual.
(Item 6)
6. The method of any one of items 1-5, wherein the tissue is contacted with the one or more FAO activators for about 72 hours or less, about 48 hours or less, or about 24 hours or less.
(Item 7)
The method according to any one of items 1 to 6, wherein said contacting is in vitro or ex vivo.
(Item 8)
7. The method according to any one of items 1 to 6, wherein said contacting is in vivo.
(Item 9)
A method of treating a tissue-related disease or condition in an individual comprising administering to said tissue of said individual an effective amount of a pharmaceutical composition comprising tissue-forming cells, wherein said tissue-forming cells are contacting one or more FAO activators prior to said administration of the therapeutic composition.
(Item 10)
10. The method of item 9, wherein the method comprises contacting the tissue-forming cells with the one or more FAO activators prior to the administration of the pharmaceutical composition.
(Item 11)
11. The method of item 9 or 10, wherein the tissue forming cells are contacted with the one or more FAO activators for no more than about 72 hours, no more than about 48 hours, or no more than about 24 hours.
(Item 12)
The method according to any one of items 9 to 11, wherein the tissue-forming cells are autologous.
(Item 13)
The method according to any one of items 9 to 11, wherein the tissue forming cells are allogeneic.
(Item 14)
A method of treating a tissue-related disease or condition in an individual, said method comprising administering to said individual an effective amount of a pharmaceutical composition comprising one or more FAO activators.
(Item 15)
The method according to any one of items 9 to 14, wherein the disease or condition is tissue injury.
(Item 16)
The method according to any one of items 9 to 15, wherein the disease or condition is tissue degeneration or tissue fibrosis.
(Item 17)
18. The method according to any one of items 9 to 17, wherein the disease or condition is aging.
(Item 18)
The disease or condition may include sarcopenia, cachexia, disuse atrophy, inflammatory muscle disease, muscular dystrophy, cardiomyopathy, skin wrinkles, intractable skin ulcers, skin wounds, bullosa, alopecia, keloids, dermatitis, and macula. Degeneration, colitis, fatty liver, steatohepatitis, liver fibrosis, cirrhosis, pancreatitis, type 2 diabetes (T2D), lipodystrophy, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, acute respiratory distress syndrome (ARDS), rheumatoid arthritis, osteoarthritis, osteoporosis, neurodegenerative diseases, cerebral infarction, myocardial infarction, pulmonary infarction, bone fracture, gastric ulcer, enterocolitis, chronic kidney disease, renal fibrosis, and tissues/organs/body parts. Any one of items 9 to 18 selected from the group consisting of other genetically determined, environmentally determined, or idiopathic disease processes that cause loss or atrophy of structure and function of Method described.
(Item 19)
A method of providing one or more exercise and/or nutritional benefits to the tissues of an individual, the method comprising administering to said individual an effective amount of a pharmaceutical composition comprising one or more FAO activators. Said method.
(Item 20)
The method according to any one of items 1 to 19, wherein the tissue is injured tissue.
(Item 21)
21. The method of item 20, wherein the pharmaceutical composition is administered to the individual within about 72 hours, within about 48 hours, or within about 24 hours after the tissue injury.
(Item 22)
20. The method of any one of items 1-19, wherein the tissue is undamaged.
(Item 23)
23. The method of any one of items 1-22, wherein the tissue is selected from the group consisting of muscle tissue, liver tissue, heart tissue, skin tissue, and hair follicles.
(Item 24)
24. The method according to item 23, wherein the tissue is muscle tissue.
(Item 25)
25. The method according to item 24, wherein the tissue forming cells are myogenic cells.
(Item 26)
26. The method according to item 25, wherein the myogenic cells are myoblasts and/or muscle cells.
(Item 27)
27. The method of any one of items 14-26, wherein the pharmaceutical composition is administered to the individual once every 24 hours, every 48 hours, or every 72 hours.
(Item 28)
28. The method of any one of items 14-27, wherein the pharmaceutical composition is administered to the tissue of the individual.
(Item 29)
29. The method of item 28, wherein the pharmaceutical composition is administered intramuscularly.
(Item 30)
29. The method of item 28, wherein the pharmaceutical composition is administered subcutaneously.
(Item 31)
28. The method of any one of items 14-27, wherein said pharmaceutical composition is administered systemically to said individual.
(Item 32)
The method according to any one of items 9 to 31, wherein the individual is an elderly individual.
(Item 33)
The one or more FAO activators are
(1) Increase mitochondrial FAO in myogenic cells,
(2) increase mitochondrial oxygen consumption in myogenic cells;
(3) does not affect mitochondrial biogenesis in myogenic cells;
(4) does not affect the membrane potential of myogenic cells, and/or
(5) The method according to any one of items 1 to 32, which increases the level(s) of PAX7, MyoD, Ki67, MyoG, Myh3, PPARγ, PPARα, and/or H3K9ac in myogenic cells.
(Item 34)
34. The method according to any one of items 1 to 33, wherein the one or more FAO activators include activators of genes in the FAO pathway or lipid metabolic pathway.
(Item 35)
The one or more FAO activators are transcriptional regulators of lipid metabolism, fatty acid transporters, lipases, carnitine palmitoyl-transferases, carnitine acetylase, acyl-CoA dehydrogenases, hydroxyacyl-CoA dehydrogenases, and mitochondrial electron transport flavoproteins. 35. The method according to any one of items 1 to 34, comprising an activator of a gene selected from the group consisting of.
(Item 36)
The one or more FAO activators are PPARα, PPARδ, PPARγ, RXRB, RXRG, NCOA1, NCOA2, FABP3, FABP4, CD36, SCARB1, FATP1, FATP2, FATP3, FATP4, FATP5, FATP6, LPL, CPT1 A.CPT1B , CPT1C, CPT2, CRAT, ACAD1, ACAD2, ACAD3, ACAD4, ACAD5, ACAD6, ACAD7, ACAD8, ACAD9, ACAD10, ACAD11, MCAD, LCAD, VLCAD, HADHA, HADHB, ETFA, and ET selected from the group consisting of FB The method according to item 35, comprising a gene activator.
(Item 37)
37. The method of any one of items 1-36, wherein the one or more FAO activators include one or more PPARγ activators.
(Item 38)
A method of increasing FAO in tissue-forming cells, the method comprising contacting the tissue-forming cells with one or more PPARγ activators for up to about 72 hours.
(Item 39)
A method for activating PPARγ in tissue-forming cells, the tissue-forming cells being treated with prostaglandin I2 (PGI2), prostaglandin D2 (PGD2), analogs thereof, and salts and solvates thereof. , tautomers and stereoisomers.
(Item 40)
40. The method according to any one of item 38 or 39, wherein the tissue forming cells are myogenic cells.
(Item 41)
41. The method according to item 40, wherein the myogenic cells are myoblasts or muscle cells.
(Item 42)
The method of any one of items 37-38 and 40-41, wherein the one or more PPARγ activators comprise a PPARγ agonist.
(Item 43)
43. The method according to item 42, wherein the PPARγ agonist is a thiazolidinedione or a derivative thereof, or a salt, solvate, tautomer or stereoisomer thereof.
(Item 44)
44. The method according to item 43, wherein the PPARγ agonist is rosiglitazone, or a salt, solvate, tautomer or stereoisomer thereof.
(Item 45)
the one or more PPARγ activators comprise prostaglandins selected from the group consisting of PGI2, PGD2, analogs thereof, and salts, solvates, tautomers and stereoisomers thereof; The method according to any one of items 37 to 38 and 40 to 44.
(Item 46)
The method according to any one of items 39 to 41 and 45, wherein the prostaglandin is PGI2, or a salt, solvate, tautomer or stereoisomer thereof.
(Item 47)
47. The method of item 46, wherein the one or more PPARγ activators are rosiglitazone and PGI2.
(Item 48)
The method according to any one of items 39 to 41 and 45, wherein the prostaglandin is treprostinil, or a salt, solvate, tautomer or stereoisomer thereof.
(Item 49)
49. The method of item 48, wherein the one or more PPARγ activators are rosiglitazone and treprostinil.
(Item 50)
A pharmaceutical composition comprising tissue-forming cells, wherein the tissue-forming cells are contacted with one or more FAO activators for about 72 hours or less.
Claims (45)
(ii)前記接触させることが、インビボ、インビトロもしくはエクスビボである、
請求項1~5のいずれか1項に記載の組成物。 (i) said tissue contacts said one or more FAO activators for no more than about 72 hours, no more than about 48 hours, or no more than about 24 hours; and/or
(ii) said contacting is in vivo, in vitro or ex vivo;
The composition according to any one of claims 1 to 5.
(i)約72時間以下、約48時間以下、または約24時間以下、前記1つ以上のFAO活性化因子と接触する、及び/または
(ii)自己性もしくは同種異系である、
請求項7または8に記載の使用のための薬学的組成物。 The tissue forming cells are
(i) contacting said one or more FAO activators for no more than about 72 hours, no more than about 48 hours, or no more than about 24 hours; and/or
(ii) is autologous or allogeneic;
Pharmaceutical composition for use according to claim 7 or 8 .
(1)筋原性細胞におけるミトコンドリアFAOを増加させる、
(2)筋原性細胞におけるミトコンドリア酸素消費量を増加させる、
(3)筋原性細胞におけるミトコンドリア生物発生に影響を及ぼさない、
(4)筋原性細胞の膜電位に影響を及ぼさない、及び/または
(5)筋原性細胞におけるPAX7、MyoD、Ki67、MyoG、Myh3、MYH7、MYH8、MHC、α-アクチニン、PPARγ、PPARα、及びH3K9acのレベル(複数可)のうちの1つ以上を増加させる、請求項1~28のいずれか1項に記載の組成物または使用のための薬学的組成物。 The one or more FAO activators are
(1) Increase mitochondrial FAO in myogenic cells,
(2) increase mitochondrial oxygen consumption in myogenic cells;
(3) does not affect mitochondrial biogenesis in myogenic cells;
(4) Does not affect the membrane potential of myogenic cells, and/or (5) PAX7, MyoD, Ki67, MyoG, Myh3, MYH7, MYH8, MHC, α-actinin, PPARγ, PPARα in myogenic cells 29. A composition or pharmaceutical composition for use according to any one of claims 1 to 28 , which increases one or more of the following: , and the level(s) of H 3K9ac.
(i)FAO経路または脂質代謝経路における遺伝子の活性化因子、ならびに/または
(ii)脂質代謝の転写調節因子、脂肪酸輸送体、リパーゼ、カルニチンパルミトイル-トランスフェラーゼ、カルニチンアセチラーゼ、アシル-CoAデヒドロゲナーゼ、ヒドロキシアシル-CoAデヒドロゲナーゼ、及びミトコンドリア電子伝達フラボタンパク質からなる群から選択される遺伝子の活性化因子
を含む、請求項1~29のいずれか1項に記載の組成物または使用のための薬学的組成物。 The one or more FAO activators are
(i) an activator of a gene in the FAO pathway or lipid metabolic pathway; and/or
(ii) a gene selected from the group consisting of transcriptional regulators of lipid metabolism, fatty acid transporters, lipases, carnitine palmitoyl-transferases, carnitine acetylase, acyl-CoA dehydrogenases, hydroxyacyl-CoA dehydrogenases, and mitochondrial electron transfer flavoproteins; activator of
A composition or a pharmaceutical composition for use according to any one of claims 1 to 29 , comprising:
(i)PPARγアゴニスト、及び/または
(ii)PGI2、PGD2、またはそれらの類似体、それらの塩、それらの溶媒和物、それらの互変異性体もしくはそれらの立体異性体からなる群から選択されるプロスタグランジン
を含む、請求項32、33及び35~37のいずれか1項に記載の組成物または使用のための薬学的組成物。 The one or more PPARγ activators are
(i) a PPARγ agonist , and/or
(ii) a prostaglandin selected from the group consisting of PGI2, PGD2, or analogs thereof, salts thereof, solvates thereof, tautomers thereof or stereoisomers thereof;
A composition or a pharmaceutical composition for use according to any one of claims 32, 33 and 35-37, comprising:
(ii)前記プロスタグランジンが、PGI2、またはその塩、その溶媒和物、その互変異性体もしくはその立体異性体である、または前記プロスタグランジンが、トレプロスチニル、またはその塩、その溶媒和物、その互変異性体もしくはその立体異性体である、
請求項38に記載の組成物または使用のための薬学的組成物。 (i) the PPARγ agonist is a thiazolidinedione or a derivative thereof, a salt thereof , a solvate thereof, a tautomer thereof or a stereoisomer thereof; and/or
(ii) the prostaglandin is PGI2, a salt thereof, a solvate thereof, a tautomer or a stereoisomer thereof, or the prostaglandin is treprostinil, a salt thereof, a solvate thereof; , its tautomer or its stereoisomer,
39. A composition or pharmaceutical composition for use according to claim 38 .
a)チアゾリジンジオンまたはその誘導体、その塩、その溶媒和物、その互変異性体もしくはその立体異性体、およびa) Thiazolidinedione or its derivative, its salt, its solvate, its tautomer or its stereoisomer, and
b)プロスタグランジンまたはその類似体、その塩、その溶媒和物、その互変異性体もしくはその立体異性体b) Prostaglandin or its analog, its salt, its solvate, its tautomer or its stereoisomer
を含む、請求項32、33及び35~40のいずれか一項に記載の組成物または使用のための薬学的組成物。A composition or a pharmaceutical composition for use according to any one of claims 32, 33 and 35-40, comprising:
(i)ロシグリタゾン及びPGI2、または
(ii)ロシグリタゾン及びトレプロスチニル
を含む、請求項32、33及び35~41のいずれか一項に記載の組成物または使用のための薬学的組成物。 The one or more PPARγ activators are
(i) rosiglitazone and PGI2, or
(ii) Rosiglitazone and Treprostinil
A composition or a pharmaceutical composition for use according to any one of claims 32, 33 and 35-41, comprising :
(i)ロシグリタゾン及びPGI2、または(i) rosiglitazone and PGI2, or
(ii)ロシグリタゾン及びトレプロスチニル(ii) Rosiglitazone and Treprostinil
を含む、請求項43または44に記載のキット。45. The kit according to claim 43 or 44, comprising:
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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CN2019105890 | 2019-09-16 | ||
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US20170296588A1 (en) * | 2016-04-19 | 2017-10-19 | AngioStem, Inc. | Mesenchymal stem cells derived from placental sources |
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