Comparing non-inbred autologous and allogeneic induced pluripotent stem cells (iPSCs) and their secreted subcellular products among non-human primates is critical for choosing optimal iPSC products for human clinical trials. Methods: iPSCs were induced from skin fibroblastic cells of adult male rhesus macaques belonging to four unrelated consanguineous families. Teratoma generativity, host immune response, and skin wound healing promotion were evaluated subsequently. Findings: All autologous, but no allogeneic, iPSCs formed teratomas, whereas all allogeneic, but no autologous, iPSCs caused lymphocyte infiltration. Macrophages were not detectable in any wound. iPSCs expressed significantly more MAMU A and E of the major histocompatibility complex (MHC) class I but not more other MHC genetic alleles than parental fibroblastic cells. All topically disseminated autologous and allogeneic iPSCs, and their exosomes accelerated skin wound healing, as demonstrated by wound closure, epithelial coverage, collagen deposition, and angiogenesis. Allogeneic iPSCs and their exosomes were less effective and viable than their autologous counterparts. Some iPSCs differentiated into new endothelial cells and all iPSCs lost their pluripotency in 14 days. Exosomes increased cell viability of injured epidermal, endothelial, and fibroblastic cells in vitro. Although exosomes contained some mRNAs of pluripotent factors, they did not impart pluripotency to host cells. Interpretation: Although all of the autologous and allogeneic iPSCs and exosomes accelerated wound healing, allogeneic iPSC exosomes were the preferred choice for "off-the shelf" iPSC products, owing to their massproduction, with no concern of teratoma formation. Fund: National Natural Science Foundation of China and National Key R&D Program of China.

No abstract

This study aimed to determine the mechanism of isogeneic-induced pluripotent stem cells (iPSCs) homing to vascular transplants and their therapeutic effect on chronic allogeneic vasculopathy. We found that integrin β1 (Intgβ1) was the dominant integrin β unit in iPSCs that mediates the adhesion of circulatory and endothelial cells (ECs). Intgβ1 knockout or Intgβ1-siRNAs inhibit iPSC adhesion and migration across activated endothelial monolayers. The therapeutic effects of the following were examined: iPSCs, Intgβ1-knockout iPSCs, iPSCs transfected with Intgβ1-siRNAs or nontargeting siRNAs, iPSC-derived ECs, iPSC-derived ECs simultaneously overexpressing Intgα4 and Intgβ1, iPSCs precultured in endothelial medium for 3 days (endothelialprone stem cells), primary aortic ECs, mouse embryonic fibroblasts, and phosphatebuffered saline (control). The cells were administered every 3 days for a period of 8 weeks. iPSCs, iPSCs transfected with nontargeting siRNAs, and endothelial-prone stem cells selectively homed on the luminal surface of the allografts, differentiated into ECs, and decreased neointimal proliferation. Through a single administration, we found that iPSCs trafficked to allograft lesions, differentiated into ECs within 1 week, and survived for 4-8 weeks. The therapeutic effect of a single administration was moderate. Thus, Intgβ1 and pluripotency are essential for iPSCs to treat allogeneic vasculopathy.

No abstract

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by an autoimmune-mediated loss of insulin secreting β-cells. Each B lymphocyte clone that escapes immune tolerance produces a specific antibody. No specific treatment against autoantibodies is available for autoimmune diseases. We have developed a strategy to produce an antiserum against autoantibodies for the treatment of T1DM. Non-obese diabetic (NOD) but not Balb/c mouse serum contains autoantibodies. Antisera were produced by immunizing Balb/c mice with affinity-purified IgG from NOD or BALB/c mice along with the immune adjuvant (hereafter, NIgG or BIgG, respectively). A bolus administration of NIgG significantly reduced serum autoantibodies, autoantibody-positive B lymphocytes in the spleens of NOD mice, mortality and morbidity of diabetes, blood glucose and islet immune infiltration, whereas it increased islet mass in NOD mice for at least 26 weeks. NIgG antiserum treatment has no significant effect on CD3(+), CD4(+) or CD8(+) T cells and B220(+) or CD19(+) B cells. BIgG also imparted a moderate therapeutic effect, although it was considerably lower than that of NIgG. NIgG did not cross-react with allogeneic serum. NIgG showed no effect on Balb/c mice. The results show the feasibility of producing antiserum against autoantibodies to prevent and treat autoimmune-induced T1DM with a single bolus administration.