Biology subjects

Assi, R.

Publications and source records attributed to Assi, R..

6 recordsLinked to original sources

bioRxiv2026

Hydraulic fracturing-induced delamination and extravasation extends medial damage beyond the false lumen in aortic dissection

Aortic dissection is life-threatening due to continued loss of medial integrity that may culminate in secondary rupture within hours to days. While pre-existing defects or hemodynamic loads compound structural deterioration of the aorta, pathological progression from symptomatic dissection channel to lethal transmural tear is poorly understood. We examined the structure of referent and acutely dissected ascending aortas by microscopy. Elastic, collagen, and cellular components of non-dissected media were intricately interconnected. Medial damage in dissection lesions was traced from ingress to central to peripheral areas. Entry tears broke cleanly through successive laminae leading to cavernous false lumens in which medial structure was destroyed. Nearby laminae with widening between flanking elastic lamellae (termed minor delaminations) were filled with blood and showed severe medial damage. Farther laminae without delamination but containing red blood cells (termed blood extravasation) displayed moderate medial damage. More distant, non-delaminated laminae with accumulation of albumin but not red blood cells (termed plasma extravasation) exhibited mild medial damage. Varying medial hemorrhage with scattered sloughing of laminae was observed along the entire false lumen. We conclude that hydraulic fracturing of residual dissected media by pressurized blood via communications from the false lumen contributes to further structural weakening of the aortic wall.

pathology↗

bioRxiv2026

Increased medial collagen enhances aortic resilience against mural delamination from hydraulic fracturing

The aorta, normally resilient to hemodynamic stresses, becomes vulnerable to structural failure due to diverse conditions that weaken the wall. We injected fluid into excised specimens of human ascending aorta with pressure monitoring to quantify the impact of clinical and histological factors on mural damage. Two modes of medial injury emerged with distinct pressure tracings. Extravasation was characterized by diffuse infiltration of fluid with widespread damage of smooth muscle cells and collagen fibers but limited separation of elastic lamellae. By contrast, delamination was characterized by marked separation of elastic lamellae along a single plane with damage to cells and fibrillar matrix restricted to adjacent laminae. Aging, aortic dilatation, and family history associated with lower pressures causing delamination, whereas a diagnosis of hypertension associated with higher pressures suggesting resilience to dissection. Collagen fraction adjacent to delamination correlated with higher pressures as did decreased smooth muscle cell density and increased glycosaminoglycan fraction, although several clinical and histological variables were interrelated. Protein cross-linking strengthened and enzymatic digestion of collagen weakened the aortic wall, while acute cell lysis with detergent had no effect. We conclude that increased functional medial collagen has an adaptive protective role in aortic remodeling rather than signifying medial degeneration.

bioengineering↗

bioRxiv2025

Mechanisms Driving Thoracic Aortic Aneurysm Stability

Thoracic aortic aneurysms (TAAs) arise from a combination of biological and mechanical factors. Current clinical guidelines use size and rate of expansion to stratify risk, but such metrics do not predict if an aneurysm will stabilize, grow, dissect, or rupture. Computational biomechanical models can provide insights into mechanisms of aneurysm behavior that would be difficult or impossible to capture in vivo. Here, we use a constrained mixture theory of growth and remodeling to simulate lesion progression while co-varying rate-dependent parameters that contribute to the natural history of aneurysm growth. This includes insults to the material structure and mechanosensitivity of the vessel. This framework successfully simulates clinically-relevant phenotypes, including cases where lesions with initially similar degrees of dilatation or rates of expansion diverge in behavior later in their progression. By capturing this spectrum of outcomes, our framework lays a foundation for more accurate, patient-specific risk prediction and future integration of machine learning tools to accelerate translation into clinical practice.

bioengineering↗

bioRxiv2025

Cryo-mtscATAC-seq for single-cell mitochondrial DNA genotyping and clonal tracing in archived human tissues

High-throughput clonal tracing of primary human samples relies on naturally occurring barcodes, such as somatic mitochondrial DNA (mtDNA) mutations detected via single-cell ATAC-seq (mtscATAC-seq). Fresh-frozen clinical specimens preserve tissue architecture but compromise cell integrity, thereby precluding their use in multi- omic approaches such as mitochondrial genotyping at single-cell resolution. Here, we introduce Cryo-mtscATAC-seq, a broadly applicable method for diverse pathophysiological contexts to isolate nuclei with their associated mitochondria ("CryoCells") from frozen samples for high-throughput clonal analysis. We applied Cryo-mtscATAC-seq to the neurodegenerated human brain, glioblastoma (GBM), pediatric neuroblastoma, and human aorta, and implemented mitobender, a computational tool to reduce ambient mtDNA in single-cell assays. Our approach revealed regional clonal gliogenesis and microglial expansions in amyotrophic lateral sclerosis (ALS), persistence of oligodendrocyte progenitor cell (OPC)-like clones in GBM recurrence, mtDNA depth heterogeneity after neuroblastoma chemotherapy, and oligoclonal proliferation of smooth muscle cells in human aorta. In conclusion, Cryo-mtscATAC-seq broadly extends mtDNA genotyping to archival frozen specimens across tissue types, opening new avenues for investigation of cell state- informed clonality in human health and disease.

systems biology↗

bioRxiv2024

Heterogeneous Cardiac- and Neural Crest-Derived Aortic Smooth Muscle Cells have Similar Transcriptional Changes after TGFβ Signaling Disruption

Smooth muscle cells (SMCs) of cardiac and neural crest origin contribute to the developing proximal aorta and are linked to disease propensity in adults. We analyzed single-cell transcriptomes of SMCs from mature thoracic aortas in mice to determine basal states and changes after disrupting transforming growth factor-{beta} (TGF{beta}) signaling necessary for aortic homeostasis. A minority of Myh11 lineage-marked SMCs differentially expressed genes suggestive of embryological origin. Additional analyses in Nkx2-5 and Wnt1 lineage-marked SMCs derived from cardiac and neural crest progenitors, respectively, showed both lineages contributed to a major common cluster and each lineage to a minor distinct cluster. Common cluster SMCs extended from root to arch, cardiac subset cluster SMCs from root to mid-ascending, while neural crest subset cluster SMCs were restricted to the arch. The neural crest subset cluster had greater expression of a subgroup of TGF{beta}-dependent genes suggesting specific responsiveness or skewed extracellular matrix synthesis. Nonetheless, deletion of TGF{beta} receptors in SMCs resulted in similar transcriptional changes among all clusters, primarily decreased extracellular matrix molecules and modulators of TGF{beta} signaling. Many embryological markers of murine aortic SMCs were not confirmed in adult human aortas. We conclude: (i) there are multiple subtypes of cardiac- and neural crest-derived SMCs with shared or distinctive transcriptional profiles, (ii) neural crest subset SMCs with increased expression of certain TGF{beta}-inducible genes are not spatially linked to the aortic root predisposed to aneurysms from aberrant TGF{beta} signaling, and (iii) loss of TGF{beta} responses after receptor deletion is uniform among SMCs of different embryological origins.

pathology↗

bioRxiv2024

Short-Term Disruption of TGFβ Signaling in Adult Mice Renders the Aorta Vulnerable to Hypertension-Induced Dissection

Hypertension and transient increases in blood pressure from extreme exertion are risk factors for aortic dissection in patients with age-related vascular degeneration or inherited connective tissue disorders. Yet, the common experimental model of angiotensin II-induced aortopathy in mice appears independent of high blood pressure as lesions do not occur in response to an alternative vasoconstrictor, norepinephrine, and are not prevented by co-treatment with a vasodilator, hydralazine. We investigated vasoconstrictor administration to adult mice 1 week after disruption of TGF{beta} signaling in smooth muscle cells. Norepinephrine increased blood pressure and induced aortic dissection by 7 days and even within 30 minutes that was rescued by hydralazine; results were similar with angiotensin II. Changes in regulatory contractile molecule expression were not of pathological significance. Rather, reduced synthesis of extracellular matrix yielded a vulnerable aortic phenotype by decreasing medial collagen, most dynamically type XVIII, and impairing cell-matrix adhesion. We conclude that transient and sustained increases in blood pressure cause dissection in aortas rendered vulnerable by inhibition of TGF{beta}-driven extracellular matrix production by smooth muscle cells. A corollary is that medial fibrosis, a frequent feature of medial degeneration, may afford some protection against aortic dissection.

pathology↗