Non-invasive quantification of stem cell-derived islet graft size and composition

Vaeinoe Lithovius; Salla Lahdenpohja; Hazem Ibrahim; Jonna Saarimaki-Vire; Lotta Uusitalo; Hossam Montaser; Kirsi Mikkola; Cheng-Bin Yim; Thomas Keller; Johan Rajander; Diego Balboa; Tom Barsby; Olof Solin; Pirjo Nuutila; Tove J. Gronroos; Timo Otonkoski

doi:10.1007/s00125-024-06194-5

Non-invasive quantification of stem cell-derived islet graft size and composition

Vaeinoe Lithovius
, Salla Lahdenpohja
, Hazem Ibrahim
, Jonna Saarimaki-Vire
, Lotta Uusitalo
, Hossam Montaser
, Kirsi Mikkola
, Cheng-Bin Yim
, Thomas Keller
, Johan Rajander
, Diego Balboa
, Tom Barsby
, Olof Solin
, Pirjo Nuutila
, Tove J. Gronroos
, Timo Otonkoski

Turku PET Centre

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

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Abstract

Aims/hypothesis: Stem cell-derived islets (SC-islets) are being used as cell replacement therapy for insulin-dependent diabetes. Non-invasive long-term monitoring methods for SC-islet grafts, which are needed to detect misguided differentiation in vivo and to optimise their therapeutic effectiveness, are lacking. Positron emission tomography (PET) has been used to monitor transplanted primary islets. We therefore aimed to apply PET as a non-invasive monitoring method for SC-islet grafts. Methods: We implanted different doses of human SC-islets, SC-islets derived using an older protocol or a state-of-the-art protocol and SC-islets genetically rendered hyper- or hypoactive into mouse calf muscle to yield different kinds of grafts. We followed the grafts with PET using two tracers, glucagon-like peptide 1 receptor-binding [ ¹⁸F]F-dibenzocyclooctyne-exendin-4 ([ ¹⁸F]exendin) and the dopamine precursor 6-[ ¹⁸F]fluoro-l-3,4-dihydroxyphenylalanine ([ ¹⁸F]FDOPA), for 5 months, followed by histological assessment of graft size and composition. Additionally, we implanted a kidney subcapsular cohort with different SC-islet doses to assess the connection between C-peptide and stem cell-derived beta cell (SC-beta cell) mass. Results: Small but pure and large but impure grafts were derived from SC-islets. PET imaging allowed detection of SC-islet grafts even <1 mm ³ in size, [ ¹⁸F]exendin having a better detection rate than [ ¹⁸F]FDOPA (69% vs 44%, <1 mm ³; 96% vs 85%, >1 mm ³). Graft volume quantified with [ ¹⁸F]exendin (r ²=0.91) and [ ¹⁸F]FDOPA (r ²=0.86) strongly correlated with actual graft volume. [ ¹⁸F]exendin PET delineated large cystic structures and its uptake correlated with graft SC-beta cell proportion (r ²=0.68). The performance of neither tracer was affected by SC-islet graft hyper- or hypoactivity. C-peptide measurements under fasted or glucose-stimulated conditions did not correlate with SC-islet graft volume or SC-beta cell mass, with C-peptide under hypoglycaemia having a weak correlation with SC-beta cell mass (r ²=0.52). Conclusions/interpretation: [ ¹⁸F]exendin and [ ¹⁸F]FDOPA PET enable non-invasive assessment of SC-islet graft size and aspects of graft composition. These methods could be leveraged for optimising SC-islet cell replacement therapy in diabetes. Graphical Abstract: (Figure presented.)

Original language	English
Pages (from-to)	1912-1929
Number of pages	18
Journal	Diabetologia
Volume	67
Issue number	9
DOIs	https://doi.org/10.1007/s00125-024-06194-5
Publication status	Published - Sept 2024
MoE publication type	A1 Journal article-refereed

Funding

Open Access funding provided by University of Helsinki (including Helsinki University Central Hospital).The Otonkoski laboratory has received funding for this study from: the Academy of Finland (grant 297466) and as its Center of Excellence (MetaStem, grant 312437), the Sigrid Jus\u00E9lius Foundation, the Novo Nordisk Foundation and the Helsinki University Hospital Funds. The Nuutila group/Turku PET Centre has received funding for this study from: the Academy of Finland CoE, European Commission FP7 programmes BetaImage (222980) and BetaCure (602812), and the Novo Nordisk Foundation. The Solin group/Turku PET Centre has received funding for this study from: the Academy of Finland (266891 and 334310) and the Swedish Cultural Foundation in Finland (151484). VL has received personal grant support from the Emil Aaltonen Foundation, Orion Research Foundation, the Finnish Medical Foundation, the Maud Kuistila Memorial Foundation, the Ida Montin Foundation and the Biomedicum Helsinki Foundation, and gratefully acknowledges their support.

Keywords

Beta cell mass
Cell replacement therapy
Congenital hyperinsulinism
Pet
Positron emission tomography
Stem cell-derived islets
Transplantation
Type 1 diabetes

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s00125-024-06194-5Final published version, 3.44 MBLicence: CC BY

https://urn.fi/URN:NBN:fi-fe2024120499322

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Lithovius, V., Lahdenpohja, S., Ibrahim, H., Saarimaki-Vire, J., Uusitalo, L., Montaser, H., Mikkola, K., Yim, C.-B., Keller, T., Rajander, J., Balboa, D., Barsby, T., Solin, O., Nuutila, P., Gronroos, T. J., & Otonkoski, T. (2024). Non-invasive quantification of stem cell-derived islet graft size and composition. Diabetologia, 67(9), 1912-1929. https://doi.org/10.1007/s00125-024-06194-5

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abstract = "Aims/hypothesis: Stem cell-derived islets (SC-islets) are being used as cell replacement therapy for insulin-dependent diabetes. Non-invasive long-term monitoring methods for SC-islet grafts, which are needed to detect misguided differentiation in vivo and to optimise their therapeutic effectiveness, are lacking. Positron emission tomography (PET) has been used to monitor transplanted primary islets. We therefore aimed to apply PET as a non-invasive monitoring method for SC-islet grafts. Methods: We implanted different doses of human SC-islets, SC-islets derived using an older protocol or a state-of-the-art protocol and SC-islets genetically rendered hyper- or hypoactive into mouse calf muscle to yield different kinds of grafts. We followed the grafts with PET using two tracers, glucagon-like peptide 1 receptor-binding [ 18F]F-dibenzocyclooctyne-exendin-4 ([ 18F]exendin) and the dopamine precursor 6-[ 18F]fluoro-l-3,4-dihydroxyphenylalanine ([ 18F]FDOPA), for 5 months, followed by histological assessment of graft size and composition. Additionally, we implanted a kidney subcapsular cohort with different SC-islet doses to assess the connection between C-peptide and stem cell-derived beta cell (SC-beta cell) mass. Results: Small but pure and large but impure grafts were derived from SC-islets. PET imaging allowed detection of SC-islet grafts even <1 mm 3 in size, [ 18F]exendin having a better detection rate than [ 18F]FDOPA (69\% vs 44\%, <1 mm 3; 96\% vs 85\%, >1 mm 3). Graft volume quantified with [ 18F]exendin (r 2=0.91) and [ 18F]FDOPA (r 2=0.86) strongly correlated with actual graft volume. [ 18F]exendin PET delineated large cystic structures and its uptake correlated with graft SC-beta cell proportion (r 2=0.68). The performance of neither tracer was affected by SC-islet graft hyper- or hypoactivity. C-peptide measurements under fasted or glucose-stimulated conditions did not correlate with SC-islet graft volume or SC-beta cell mass, with C-peptide under hypoglycaemia having a weak correlation with SC-beta cell mass (r 2=0.52). Conclusions/interpretation: [ 18F]exendin and [ 18F]FDOPA PET enable non-invasive assessment of SC-islet graft size and aspects of graft composition. These methods could be leveraged for optimising SC-islet cell replacement therapy in diabetes. Graphical Abstract: (Figure presented.)",

keywords = "Beta cell mass, Cell replacement therapy, Congenital hyperinsulinism, Pet, Positron emission tomography, Stem cell-derived islets, Transplantation, Type 1 diabetes",

author = "Vaeinoe Lithovius and Salla Lahdenpohja and Hazem Ibrahim and Jonna Saarimaki-Vire and Lotta Uusitalo and Hossam Montaser and Kirsi Mikkola and Cheng-Bin Yim and Thomas Keller and Johan Rajander and Diego Balboa and Tom Barsby and Olof Solin and Pirjo Nuutila and Gronroos, \{Tove J.\} and Timo Otonkoski",

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doi = "10.1007/s00125-024-06194-5",

language = "English",

volume = "67",

pages = "1912--1929",

journal = "Diabetologia",

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number = "9",

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Lithovius, V, Lahdenpohja, S, Ibrahim, H, Saarimaki-Vire, J, Uusitalo, L, Montaser, H, Mikkola, K, Yim, C-B, Keller, T, Rajander, J, Balboa, D, Barsby, T, Solin, O, Nuutila, P, Gronroos, TJ & Otonkoski, T 2024, 'Non-invasive quantification of stem cell-derived islet graft size and composition', Diabetologia, vol. 67, no. 9, pp. 1912-1929. https://doi.org/10.1007/s00125-024-06194-5

TY - JOUR

T1 - Non-invasive quantification of stem cell-derived islet graft size and composition

AU - Lithovius, Vaeinoe

AU - Lahdenpohja, Salla

AU - Ibrahim, Hazem

AU - Saarimaki-Vire, Jonna

AU - Uusitalo, Lotta

AU - Montaser, Hossam

AU - Mikkola, Kirsi

AU - Yim, Cheng-Bin

AU - Keller, Thomas

AU - Rajander, Johan

AU - Balboa, Diego

AU - Barsby, Tom

AU - Solin, Olof

AU - Nuutila, Pirjo

AU - Gronroos, Tove J.

AU - Otonkoski, Timo

PY - 2024/9

Y1 - 2024/9

N2 - Aims/hypothesis: Stem cell-derived islets (SC-islets) are being used as cell replacement therapy for insulin-dependent diabetes. Non-invasive long-term monitoring methods for SC-islet grafts, which are needed to detect misguided differentiation in vivo and to optimise their therapeutic effectiveness, are lacking. Positron emission tomography (PET) has been used to monitor transplanted primary islets. We therefore aimed to apply PET as a non-invasive monitoring method for SC-islet grafts. Methods: We implanted different doses of human SC-islets, SC-islets derived using an older protocol or a state-of-the-art protocol and SC-islets genetically rendered hyper- or hypoactive into mouse calf muscle to yield different kinds of grafts. We followed the grafts with PET using two tracers, glucagon-like peptide 1 receptor-binding [ 18F]F-dibenzocyclooctyne-exendin-4 ([ 18F]exendin) and the dopamine precursor 6-[ 18F]fluoro-l-3,4-dihydroxyphenylalanine ([ 18F]FDOPA), for 5 months, followed by histological assessment of graft size and composition. Additionally, we implanted a kidney subcapsular cohort with different SC-islet doses to assess the connection between C-peptide and stem cell-derived beta cell (SC-beta cell) mass. Results: Small but pure and large but impure grafts were derived from SC-islets. PET imaging allowed detection of SC-islet grafts even <1 mm 3 in size, [ 18F]exendin having a better detection rate than [ 18F]FDOPA (69% vs 44%, <1 mm 3; 96% vs 85%, >1 mm 3). Graft volume quantified with [ 18F]exendin (r 2=0.91) and [ 18F]FDOPA (r 2=0.86) strongly correlated with actual graft volume. [ 18F]exendin PET delineated large cystic structures and its uptake correlated with graft SC-beta cell proportion (r 2=0.68). The performance of neither tracer was affected by SC-islet graft hyper- or hypoactivity. C-peptide measurements under fasted or glucose-stimulated conditions did not correlate with SC-islet graft volume or SC-beta cell mass, with C-peptide under hypoglycaemia having a weak correlation with SC-beta cell mass (r 2=0.52). Conclusions/interpretation: [ 18F]exendin and [ 18F]FDOPA PET enable non-invasive assessment of SC-islet graft size and aspects of graft composition. These methods could be leveraged for optimising SC-islet cell replacement therapy in diabetes. Graphical Abstract: (Figure presented.)

AB - Aims/hypothesis: Stem cell-derived islets (SC-islets) are being used as cell replacement therapy for insulin-dependent diabetes. Non-invasive long-term monitoring methods for SC-islet grafts, which are needed to detect misguided differentiation in vivo and to optimise their therapeutic effectiveness, are lacking. Positron emission tomography (PET) has been used to monitor transplanted primary islets. We therefore aimed to apply PET as a non-invasive monitoring method for SC-islet grafts. Methods: We implanted different doses of human SC-islets, SC-islets derived using an older protocol or a state-of-the-art protocol and SC-islets genetically rendered hyper- or hypoactive into mouse calf muscle to yield different kinds of grafts. We followed the grafts with PET using two tracers, glucagon-like peptide 1 receptor-binding [ 18F]F-dibenzocyclooctyne-exendin-4 ([ 18F]exendin) and the dopamine precursor 6-[ 18F]fluoro-l-3,4-dihydroxyphenylalanine ([ 18F]FDOPA), for 5 months, followed by histological assessment of graft size and composition. Additionally, we implanted a kidney subcapsular cohort with different SC-islet doses to assess the connection between C-peptide and stem cell-derived beta cell (SC-beta cell) mass. Results: Small but pure and large but impure grafts were derived from SC-islets. PET imaging allowed detection of SC-islet grafts even <1 mm 3 in size, [ 18F]exendin having a better detection rate than [ 18F]FDOPA (69% vs 44%, <1 mm 3; 96% vs 85%, >1 mm 3). Graft volume quantified with [ 18F]exendin (r 2=0.91) and [ 18F]FDOPA (r 2=0.86) strongly correlated with actual graft volume. [ 18F]exendin PET delineated large cystic structures and its uptake correlated with graft SC-beta cell proportion (r 2=0.68). The performance of neither tracer was affected by SC-islet graft hyper- or hypoactivity. C-peptide measurements under fasted or glucose-stimulated conditions did not correlate with SC-islet graft volume or SC-beta cell mass, with C-peptide under hypoglycaemia having a weak correlation with SC-beta cell mass (r 2=0.52). Conclusions/interpretation: [ 18F]exendin and [ 18F]FDOPA PET enable non-invasive assessment of SC-islet graft size and aspects of graft composition. These methods could be leveraged for optimising SC-islet cell replacement therapy in diabetes. Graphical Abstract: (Figure presented.)

KW - Beta cell mass

KW - Cell replacement therapy

KW - Congenital hyperinsulinism

KW - Pet

KW - Positron emission tomography

KW - Stem cell-derived islets

KW - Transplantation

KW - Type 1 diabetes

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Non-invasive quantification of stem cell-derived islet graft size and composition

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