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. Author manuscript; available in PMC: 2019 Aug 13.
Published in final edited form as: Nature. 2019 Feb 13;567(7746):43–48. doi: 10.1038/s41586-019-0942-8

Figure 2. Insulin-producing human α-cells reverse murine diabetes.

Figure 2.

(a) Experimental design. NSG or NSG-RIP-DTR mice were made diabetic with streptozotocin (STZ) or diphtheria toxin (DT); αPM pseudoislets were transplanted under the renal capsule, either from single (Exp.#2; Extended Data Fig. 6) or multiple donors (Exps.#3 & #4; b,c). Grafts were removed after 4 weeks or up to 24 weeks in the longest experiment (“Nx” in b,c). (b) Random-fed glycemia in Exp.#3. Glycemia was decreased to normal (dotted lines) after engraftment of 6,000 pseudoislets generated from 6 donors (red line), in 3 transplantations (“Tx”: 2,150+3,100+750), like controls receiving human islets (4,000 IEQ, blue lines). Untransplanted diabetics remained hyperglycemic (black lines). n=5 (DT+noGraft), n=3 from 3 donors (DT+islets), n=1 from 6 donors (DT+αPM), n=5 mice (noDT+noGraft). (c) Random-fed glycemia in Exp.#4. 4,000 pseudoislets made from 3 donors were transplanted, leading to complete rescue. n=3 (DT+noGraft), n=2 from 2 donors (DT+islets), n=1 from 3 donors (DT+αPM), n=4 mice (noDT+noGraft). (d,e) Human C-peptide blood levels before and after glucose injection. Data from non-diabetic (d; Exps.#3,#4) and T2D donors (e; Exp.#5) are shown. n.d., undetectable. ****p<0.0001, two-way RM ANOVA with Holm-Sidak’s multiple-comparison tests. In d, n=8 (DT+noGraft), n=5 from 5 donors (DT+islets), n=1 from 6 donors (DT+αPM, Exp.#3), n=1 from 3 donors (DT+αPM, Exp.#4), n=9 mice (noDT+noGraft). In e, n=4 (STZ+noGraft), n=1 from 1 donor (STZ+islets), n=1 from 2 donors (STZ+αPM, Exp.#5), n=2 mice (noDT+noGraft). (f) Immunofluorescence on transplanted pseudoislets. Monohormonal insulin-expressing (red) α-cells (GFP+, green) are abundant. (g,h) Reprogramming efficiency (g) and percentage of monohormonal insulin-producing cells (h) in αPM pseudoislets before and after transplantation. *p=0.029, two-tailed Mann-Whitney test. n=4 donors. (i) Immunofluorescence on pseudoislets engrafted for 6-months. n=1 (6 months; i, Extended Data Fig. 6r) and n=1 (3 months; Extended Data Fig. 6q). Scale bars: 25 (f), 50 μm (i). Data are mean ± s.e.m. (d,e,g,h).