Lineage reconstruction from clonal correlations

A central task in developmental biology is to learn the sequence of fate decisions that leads to each mature cell type in a tissue or organism. Recently, clonal labeling of cells using DNA barcodes has emerged as a powerful approach for identifying cells that share a common ancestry of fate decisions. Here we explore the idea that stochasticity of cell fate choice during tissue development could be harnessed to read out lineage relationships after a single step of clonal barcoding. By considering a generalized multitype branching process, we determine the conditions under which the final distribution of barcodes over observed cell types encodes their bona fide lineage relationships. We then propose a method for inferring the order of fate decisions. Our theory predicts a set of symmetries of barcode covariance that serves as a consistency check for the validity of the method. We show that broken symmetries may be used to detect multiple paths of differentiation to the same cell types. We provide computational tools for general use. When applied to barcoding data in hematopoiesis, these tools reconstruct the classical hematopoietic hierarchy and detect couplings between monocytes and dendritic cells and between erythrocytes and basophils that suggest multiple pathways of differentiation for these lineages.

Transcriptional comparison of Testicular Adrenal Rest Tumors with fetal and adult tissues

Testicular Adrenal Rest Tumors (TART) are a common complication of unknown origin in patients with Congenital Adrenal Hyperplasia. These benign tumors may derive from cells of adrenal origin or from pluripotent progenitor cells from the fetal adrenogonadal primordium. By comparing the transcriptome of TART with fetal- and adult-testis and adrenal tissues, this study aims to unravel the origin of TART. Targeted transcriptome sequencing was followed by unsupervised clustering-, differential expression-, functional enrichment- and pathway analyses. Immunohistochemistry demonstrated co-expression of adrenal-specific CYP11B1 and testis-specific HSD17B3 in TART, indicating the existence of a distinct TART cell exhibiting both adrenal- and testicular characteristics. Principal component analysis indicated that the TART transcriptome was distinct from either adrenal or testis fetal tissue, making a progenitor-like phenotype of TART unlikely. Rather, TART appears to originate from -or differentiate into-a mature cell type, with both adrenal- and testicular characteristics. The present study, the first to describe the TART transcriptome, expands knowledge about the identity and functional characteristics of TART and identifies clinically targetable pathways associated with fibrosis.

Experimental and Computational Approaches to Direct Cell Reprogramming: Recent Advancement and Future Challenges

The process of direct cell reprogramming, also named transdifferentiation, permits for the conversion of one mature cell type directly into another, without returning to a dedifferentiated state. This makes direct reprogramming a promising approach for the development of several cellular and tissue engineering therapies. To achieve the change in the cell identity, direct reprogramming requires an arsenal of tools that combine experimental and computational techniques. In the recent years, several methods of transdifferentiation have been developed. In this review, we will introduce the concept of direct cell reprogramming and its background, and cover the recent developments in the experimental and computational prediction techniques with their applications. We also discuss the challenges of translating this technology to clinical setting, accompanied with potential solutions.

Parthenogenesis in mammals: pros and cons in pluripotent cell derivation

Embryonic stem cells (ESCs) represent a useful tool for cell therapy studies, however the use of embryos for their derivation give rise to ethical, religious and legal problems when applied to the human. During the last years parthenogenesis has been proposed as an alternative source to obtain ESCs. Based on the fact that parthenotes avoid many concerns surrounding the “ad hoc” in vitro production and following destruction of viable human embryos. Unfortunately many aspects related to parthenogenetic cell biology are not fully understood and still need to be elucidated. In this review we describe advantages and limits of these cells. We discuss their typical ESC morphology and high telomerase activity, which disappears after differentiation. We examine the pluripotency signature that they share with bi-parental ESCs. We review their high differentiation plasticity that allow for the derivation of several mature cell type populations when we expose these cells to adequate conditions. On the other hand, in-depth analysis demonstrated chromosome mal-segregation and altered mechanisms controlling centriole arrangement and mitotic spindle formation in these cells. We hypothesize their monoparental origin as one of the possible cause of these anomalies and suggest a great caution if a therapeutic use is considered.

Multipotential stem cells in adult mouse gastric epithelium

Previous studies of chimeric animals demonstrate that multipotential stem cells play a role in the development of the gastric epithelium; however, despite much effort, it is not clear whether they persist into adulthood. Here, chemical mutagenesis was used to label random epithelial cells by loss of transgene function in adult hemizygous ROSA26 mice, a mouse strain expressing the transgene lacZ in all tissues. Many clones derived from such cells contained all the major epithelial cell types, thereby demonstrating existence of functional multipotential stem cells in adult mouse gastric epithelium. We also observed clones containing only a single mature cell type, indicating the presence of long-lived committed progenitors in the gastric epithelium. Similar results were obtained in duodenum and colon, showing that this mouse model is suitable for lineage tracing in all regions of the gastrointestinal tract and likely useful for cell lineage studies in other adult renewing tissues.