blastocyst complementation
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2022 ◽  
Author(s):  
Shunsuke Yuri ◽  
Yuki Murase ◽  
Aayako Isotani

Regenerative medicine is a tool to compensate for the shortage of lungs for transplantation, but it remains difficult to construct a lung in vitro due to the complex three-dimensional structures and multiple cell types required. A blastocyst complementation method using interspecies chimeric animals has been attracting attention as a way to create complex organs in animals, but successful lung formation has not yet been achieved. Here, we applied a reverse-blastocyst complementation method to clarify the conditions required to form lungs in an Fgfr2b-deficient mouse model. We then successfully formed a rat-derived lung in the mouse model without generating a mouse line by applying a tetraploid-based organ-complementation method. Importantly, rat lung epithelial cells retained their developmental timing even in the mouse body. This result provides useful insights regarding the need to overcome the barrier of species-specific developmental timing in order to generate functional lungs in interspecies chimeras.


Development ◽  
2021 ◽  
Vol 148 (12) ◽  
Author(s):  
Canbin Zheng ◽  
Emily B. Ballard ◽  
Jun Wu

ABSTRACT Growing human organs in animals sounds like something from the realm of science fiction, but it may one day become a reality through a technique known as interspecies blastocyst complementation. This technique, which was originally developed to study gene function in development, involves injecting donor pluripotent stem cells into an organogenesis-disabled host embryo, allowing the donor cells to compensate for missing organs or tissues. Although interspecies blastocyst complementation has been achieved between closely related species, such as mice and rats, the situation becomes much more difficult for species that are far apart on the evolutionary tree. This is presumably because of layers of xenogeneic barriers that are a result of divergent evolution. In this Review, we discuss the current status of blastocyst complementation approaches and, in light of recent progress, elaborate on the keys to success for interspecies blastocyst complementation and organ generation.


Author(s):  
Fei Sun ◽  
Guolun Wang ◽  
Arun Pradhan ◽  
Kui Xu ◽  
Jose Gomez-Arroyo ◽  
...  

Background: Pulmonary hypertension (PH) is a common complication in patients with Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a severe congenital disorder associated with mutations in the FOXF1 gene. While the loss of alveolar microvasculature causes PH in ACDMPV patients, it is unknown whether increasing neonatal lung angiogenesis could prevent PH and right ventricular (RV) hypertrophy. Methods: We used echocardiography, RV catheterization, immunostaining and biochemical methods to examine lung and heart remodeling and RV output in Foxf1 WT/S52F mice carrying the S52F Foxf1 mutation (identified in ACDMPV patients). The ability of Foxf1 WT/S52F mutant embryonic stem cells (ESCs) to differentiate into respiratory cell lineages in vivo was examined using blastocyst complementation. Intravascular delivery of nanoparticles with a non-integrating Stat3 expression vector was used to improve neonatal pulmonary angiogenesis in Foxf1 WT/S52F mice and determine its effects on PH and RV hypertrophy. Results: Foxf1 WT/S52F mice developed PH and RV hypertrophy after birth. The severity of PH in Foxf1 WT/S52F mice directly correlated with mortality, low body weight, pulmonary artery muscularization and increased collagen deposition in the lung tissue. Increased fibrotic remodeling was found in human ACDMPV lungs. Mouse ESCs carrying the S52F Foxf1 mutation were used to produce chimeras via blastocyst complementation and to demonstrate that Foxf1 WT/S52F ESCs have a propensity to differentiate into pulmonary myofibroblasts. Intravascular delivery of nanoparticles carrying Stat3 cDNA protected Foxf1 WT/S52F mice from RV hypertrophy and PH, improved survival and decreased fibrotic lung remodeling. Conclusions: Nanoparticle therapies increasing neonatal pulmonary angiogenesis may be considered to prevent PH in ACDMPV.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
M. Ruiz-Estevez ◽  
A. T. Crane ◽  
P. Rodriguez-Villamil ◽  
F. L. Ongaratto ◽  
Yun You ◽  
...  

Abstract Background There are over 17,000 patients in the US waiting to receive liver transplants, and these numbers are increasing dramatically. Significant effort is being made to obtain functional hepatocytes and liver tissue that can for therapeutic use in patients. Blastocyst complementation is a challenging, innovative technology that could fundamentally change the future of organ transplantation. It requires the knockout (KO) of genes essential for cell or organ development in early stage host embryos followed by injection of donor pluripotent stem cells (PSCs) into host blastocysts to generate chimeric offspring in which progeny of the donor cells populate the open niche to develop functional tissues and organs. Methods The HHEX gene is necessary for proper liver development. We engineered loss of HHEX gene expression in early mouse and pig embryos and performed intraspecies blastocyst complementation of HHEX KO embryos with eGFP-labeled PSCs in order to rescue the loss of liver development. Results Loss of HHEX gene expression resulted in embryonic lethality at day 10.5 in mice and produced characteristics of lethality at day 18 in pigs, with absence of liver tissue in both species. Analyses of mouse and pig HHEX KO fetuses confirmed significant loss of liver-specific gene and protein expression. Intraspecies blastocyst complementation restored liver formation and liver-specific proteins in both mouse and pig. Livers in complemented chimeric fetuses in both species were comprised of eGFP-labeled donor-derived cells and survived beyond the previously observed time of HHEX KO embryonic lethality. Conclusions This work demonstrates that loss of liver development in the HHEX KO can be rescued via blastocyst complementation in both mice and pigs. This complementation strategy is the first step towards generating interspecies chimeras for the goal of producing human liver cells, tissues, and potentially complete organs for clinical transplantation.


Author(s):  
Raymond Ardaillou

Stem cells used in therapy include mainly hematopoietic stem cells (HSC) to treat aplasias, leukemias and hematological genetic diseases, and mesenchymal stem cells (MSC) produced in small quantities by the bone marrow, but also other tissues, to treat cardiac and cutaneous diseases thanks to their secretory properties of growth factors. A major step was taken with the use of embryonic (ESC) or induced pluripotent stem cells (iPS). The former are used, after isolation and differentiation, either in rare therapeutic purposes or for the in vitro screening of drugs. iPS are produced from adult cells after reprogramming and differentiation and utilized for the treatment of various diseases in autologous or allogeneic form, the second condition allowing only mass production. New lines of research are now in progress including the creation of organoids that are templates of many organs of the body and allow the process of cell organization and its perturbations to be analyzed. Creation of post-meiosis gametes (23 chromosomes) from iPS or ESC is intended to treat serious genetic diseases. Creation of human chimera by interspecies blastocyst complementation has also been studied in view of organ transplantation. It is only allowed for the implantation of human cells in animal blastocysts and prohibited for the reverse. Implantation in uterus of the modified embryos is prohibited by the French law.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Toshihiro Kobayashi ◽  
Teppei Goto ◽  
Mami Oikawa ◽  
Makoto Sanbo ◽  
Fumika Yoshida ◽  
...  

AbstractMurine animal models from genetically modified pluripotent stem cells (PSCs) are essential for functional genomics and biomedical research, which require germline transmission for the establishment of colonies. However, the quality of PSCs, and donor-host cell competition in chimeras often present strong barriers for germline transmission. Here, we report efficient germline transmission of recalcitrant PSCs via blastocyst complementation, a method to compensate for missing tissues or organs in genetically modified animals via blastocyst injection of PSCs. We show that blastocysts from germline-deficient Prdm14 knockout rats provide a niche for the development of gametes originating entirely from the donor PSCs without any detriment to somatic development. We demonstrate the potential of this approach by creating PSC-derived Pax2/Pax8 double mutant anephric rats, and rescuing germline transmission of a PSC carrying a mouse artificial chromosome. Furthermore, we generate mouse PSC-derived functional spermatids in rats, which provides a proof-of-principle for the generation of xenogenic gametes in vivo. We believe this approach will become a useful system for generating PSC-derived germ cells in the future.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Aleta R. Steevens ◽  
Matthew W. Griesbach ◽  
Yun You ◽  
James R. Dutton ◽  
Walter C. Low ◽  
...  

AbstractThis research is the first to produce induced pluripotent stem cell-derived inner ear sensory neurons in the Neurog1+/− heterozygote mouse using blastocyst complementation. Additionally, this approach corrected non-sensory deficits associated with Neurog1 heterozygosity, indicating that complementation is specific to endogenous Neurog1 function. This work validates the use of blastocyst complementation as a tool to create novel insight into the function of developmental genes and highlights blastocyst complementation as a potential platform for generating chimeric inner ear cell types that can be transplanted into damaged inner ears to improve hearing.


2021 ◽  
Author(s):  
Enhong Li ◽  
Vladimir Ustiyan ◽  
Bingqiang Wen ◽  
Gregory T. Kalin ◽  
Jeffrey A. Whitsett ◽  
...  

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