Specific mesoderm subset derived from human pluripotent stem cells ameliorates microvascular pathology in type 2 diabetic mice

Chang Hyun Gil; Dibyendu Chakraborty; Cristiano P. Vieira; Nutan Prasain; Sergio Li Calzi; Seth D. Fortmann; Ping Hu; Kimihiko Banno; Mohamed Jamal; Chao Huang; Micheli S. Sielski; Yang Lin; Xinxin Huang; Mariana D. Dupont; Jason L. Floyd; Ram Prasad; Ana Leda F. Longhini; Trevor J. McGill; Hyung Min Chung; Michael P. Murphy; Darrell N. Kotton; Michael E. Boulton; Mervin C. Yoder; Maria B. Grant

doi:10.1126/sciadv.abm5559

Specific mesoderm subset derived from human pluripotent stem cells ameliorates microvascular pathology in type 2 diabetic mice

Chang Hyun Gil, Dibyendu Chakraborty, Cristiano P. Vieira, Nutan Prasain, Sergio Li Calzi, Seth D. Fortmann, Ping Hu, Kimihiko Banno, Mohamed Jamal, Chao Huang, Micheli S. Sielski, Yang Lin, Xinxin Huang, Mariana D. Dupont, Jason L. Floyd, Ram Prasad, Ana Leda F. Longhini, Trevor J. McGill, Hyung Min Chung, Michael P. MurphyDarrell N. Kotton, Michael E. Boulton, Mervin C. Yoder, Maria B. Grant

Ophthalmology

Research output: Contribution to journal › Article › peer-review

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Abstract

Human induced pluripotent stem cells (hiPSCs) were differentiated into a specific mesoderm subset characterized by KDR+CD56+APLNR+ (KNA+) expression. KNA+ cells had high clonal proliferative potential and specification into endothelial colony-forming cell (ECFCs) phenotype. KNA+ cells differentiated into perfused blood vessels when implanted subcutaneously into the flank of nonobese diabetic/severe combined immunodeficient mice and when injected into the vitreous of type 2 diabetic mice (db/db mice). Transcriptomic analysis showed that differentiation of hiPSCs derived from diabetics into KNA+ cells was sufficient to change baseline differences in gene expression caused by the diabetic status and reprogram diabetic cells to a pattern similar to KNA+ cells derived from nondiabetic hiPSCs. Proteomic array studies performed on retinas of db/db mice injected with either control or diabetic donor- derived KNA+ cells showed correction of aberrant signaling in db/db retinas toward normal healthy retina. These data provide "proof of principle"that KNA+ cells restore perfusion and correct vascular dysfunction in db/db mice.

Original language	English (US)
Article number	eabm5559
Journal	Science Advances
Volume	8
Issue number	9
DOIs	https://doi.org/10.1126/sciadv.abm5559
State	Published - Mar 2022

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Gil, C. H., Chakraborty, D., Vieira, C. P., Prasain, N., Calzi, S. L., Fortmann, S. D., Hu, P., Banno, K., Jamal, M., Huang, C., Sielski, M. S., Lin, Y., Huang, X., Dupont, M. D., Floyd, J. L., Prasad, R., Longhini, A. L. F., McGill, T. J., Chung, H. M., ... Grant, M. B. (2022). Specific mesoderm subset derived from human pluripotent stem cells ameliorates microvascular pathology in type 2 diabetic mice. Science Advances, 8(9), Article eabm5559. https://doi.org/10.1126/sciadv.abm5559

Gil, CH, Chakraborty, D, Vieira, CP, Prasain, N, Calzi, SL, Fortmann, SD, Hu, P, Banno, K, Jamal, M, Huang, C, Sielski, MS, Lin, Y, Huang, X, Dupont, MD, Floyd, JL, Prasad, R, Longhini, ALF, McGill, TJ, Chung, HM, Murphy, MP, Kotton, DN, Boulton, ME, Yoder, MC & Grant, MB 2022, 'Specific mesoderm subset derived from human pluripotent stem cells ameliorates microvascular pathology in type 2 diabetic mice', Science Advances, vol. 8, no. 9, eabm5559. https://doi.org/10.1126/sciadv.abm5559

@article{c791eabc91cf451da859df3b28d4d410,

title = "Specific mesoderm subset derived from human pluripotent stem cells ameliorates microvascular pathology in type 2 diabetic mice",

abstract = "Human induced pluripotent stem cells (hiPSCs) were differentiated into a specific mesoderm subset characterized by KDR+CD56+APLNR+ (KNA+) expression. KNA+ cells had high clonal proliferative potential and specification into endothelial colony-forming cell (ECFCs) phenotype. KNA+ cells differentiated into perfused blood vessels when implanted subcutaneously into the flank of nonobese diabetic/severe combined immunodeficient mice and when injected into the vitreous of type 2 diabetic mice (db/db mice). Transcriptomic analysis showed that differentiation of hiPSCs derived from diabetics into KNA+ cells was sufficient to change baseline differences in gene expression caused by the diabetic status and reprogram diabetic cells to a pattern similar to KNA+ cells derived from nondiabetic hiPSCs. Proteomic array studies performed on retinas of db/db mice injected with either control or diabetic donor- derived KNA+ cells showed correction of aberrant signaling in db/db retinas toward normal healthy retina. These data provide {"}proof of principle{"}that KNA+ cells restore perfusion and correct vascular dysfunction in db/db mice.",

author = "Gil, {Chang Hyun} and Dibyendu Chakraborty and Vieira, {Cristiano P.} and Nutan Prasain and Calzi, {Sergio Li} and Fortmann, {Seth D.} and Ping Hu and Kimihiko Banno and Mohamed Jamal and Chao Huang and Sielski, {Micheli S.} and Yang Lin and Xinxin Huang and Dupont, {Mariana D.} and Floyd, {Jason L.} and Ram Prasad and Longhini, {Ana Leda F.} and McGill, {Trevor J.} and Chung, {Hyung Min} and Murphy, {Michael P.} and Kotton, {Darrell N.} and Boulton, {Michael E.} and Yoder, {Mervin C.} and Grant, {Maria B.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2022 The Authors.",

year = "2022",

month = mar,

doi = "10.1126/sciadv.abm5559",

language = "English (US)",

volume = "8",

journal = "Science Advances",

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T1 - Specific mesoderm subset derived from human pluripotent stem cells ameliorates microvascular pathology in type 2 diabetic mice

AU - Gil, Chang Hyun

AU - Chakraborty, Dibyendu

AU - Vieira, Cristiano P.

AU - Prasain, Nutan

AU - Calzi, Sergio Li

AU - Fortmann, Seth D.

AU - Hu, Ping

AU - Banno, Kimihiko

AU - Jamal, Mohamed

AU - Huang, Chao

AU - Sielski, Micheli S.

AU - Lin, Yang

AU - Huang, Xinxin

AU - Dupont, Mariana D.

AU - Floyd, Jason L.

AU - Prasad, Ram

AU - Longhini, Ana Leda F.

AU - McGill, Trevor J.

AU - Chung, Hyung Min

AU - Murphy, Michael P.

AU - Kotton, Darrell N.

AU - Boulton, Michael E.

AU - Yoder, Mervin C.

AU - Grant, Maria B.

PY - 2022/3

Y1 - 2022/3

N2 - Human induced pluripotent stem cells (hiPSCs) were differentiated into a specific mesoderm subset characterized by KDR+CD56+APLNR+ (KNA+) expression. KNA+ cells had high clonal proliferative potential and specification into endothelial colony-forming cell (ECFCs) phenotype. KNA+ cells differentiated into perfused blood vessels when implanted subcutaneously into the flank of nonobese diabetic/severe combined immunodeficient mice and when injected into the vitreous of type 2 diabetic mice (db/db mice). Transcriptomic analysis showed that differentiation of hiPSCs derived from diabetics into KNA+ cells was sufficient to change baseline differences in gene expression caused by the diabetic status and reprogram diabetic cells to a pattern similar to KNA+ cells derived from nondiabetic hiPSCs. Proteomic array studies performed on retinas of db/db mice injected with either control or diabetic donor- derived KNA+ cells showed correction of aberrant signaling in db/db retinas toward normal healthy retina. These data provide "proof of principle"that KNA+ cells restore perfusion and correct vascular dysfunction in db/db mice.

AB - Human induced pluripotent stem cells (hiPSCs) were differentiated into a specific mesoderm subset characterized by KDR+CD56+APLNR+ (KNA+) expression. KNA+ cells had high clonal proliferative potential and specification into endothelial colony-forming cell (ECFCs) phenotype. KNA+ cells differentiated into perfused blood vessels when implanted subcutaneously into the flank of nonobese diabetic/severe combined immunodeficient mice and when injected into the vitreous of type 2 diabetic mice (db/db mice). Transcriptomic analysis showed that differentiation of hiPSCs derived from diabetics into KNA+ cells was sufficient to change baseline differences in gene expression caused by the diabetic status and reprogram diabetic cells to a pattern similar to KNA+ cells derived from nondiabetic hiPSCs. Proteomic array studies performed on retinas of db/db mice injected with either control or diabetic donor- derived KNA+ cells showed correction of aberrant signaling in db/db retinas toward normal healthy retina. These data provide "proof of principle"that KNA+ cells restore perfusion and correct vascular dysfunction in db/db mice.

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JF - Science Advances

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Specific mesoderm subset derived from human pluripotent stem cells ameliorates microvascular pathology in type 2 diabetic mice

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